Chapter 43: Infections: Parasitic & Mycotic

The parasites that cause human disease represent a diverse, highly evolved and complex group of organisms. Parasitic diseases are a major cause of global pediatric morbidity and mortality, with the heaviest disease burden occurring in low- and middle-income countries. Though less common in industrialized nations, parasites represent an important class of pathogens to recognize in this setting, as both endemic and imported cases are frequently encountered in pediatric practice. Given the complexity of this category of pathogens, a framework to organize human parasites according to their major biologic classification and predominant site (intestinal vs blood/tissue) of human interaction can be useful to the learner (Table 43–1). Additionally, understanding organisms associated with potential clinical presentations of parasitic diseases can help focus the diagnostic process (Table 43–2).

Selection of Patients for Evaluation

The incidence of parasitic infections varies greatly with geographic area. Children who have traveled or lived in areas where parasitic infections are endemic are at risk for infection with a variety of intestinal and tissue parasites. Children who have resided only in developed countries are usually free of tissue parasites (with few exceptions, eg, Toxocara, Toxoplasma). Searching for intestinal parasites is expensive for the patient and time-consuming for the laboratory, and more than 90% of ova and parasite (O&P) examinations performed in the United States are negative. A frequent misperception is that intestinal helminths are common causes of diarrhea; with rare exception (eg, Trichuris dysentery syndrome) they are not. Parasitic diarrhea is almost exclusively caused by protozoa (Giardia, Cryptosporidium, Entamoeba) which are now commonly diagnosed with molecular methods. Thus, an O&P for a patient with diarrhea is rarely the correct test. It may also be more cost-effective to empirically treat symptomatic US immigrants with albendazole for common intestinal parasites and to investigate only those whose symptoms persist.

Immunodeficient children are very susceptible to protozoal intestinal infections. Multiple opportunistic pathogens are often identified, and the threshold for evaluation should be low for these children.

Specimen Processing

Many laboratories are now using PCR-based diagnostic assays for stool pathogens, which present fewer specimen handling challenges. Practitioners should contact the laboratory for proper collection procedures for diagnostic testing that requires microscopy, or a fresh sample to visualize viable parasites such as Giardia trophozoites. Many laboratories will reject formed stool samples submitted for parasites which cause diarrhea. The US Centers for Disease Control and Prevention (CDC) provide a website (http://dpd.cdc.gov/dpdx) to assist in the laboratory diagnosis of common parasitic diseases, including specimen collection and processing.

Eosinophilia & Parasitic Infections

Although certain parasites commonly cause eosinophilia, in developed countries other causes are much more common. These include allergies, drugs, and other infections. Nor do all parasitic infections result in eosinophilia. Eosinophilia due to parasitic infection is most common when multicellular organisms are migrating through host tissues (eg, lymphatic filariasis, hookworm). The unicellular protozoa (eg, malaria, leishmaniasis) rarely cause eosinophilia, even when infection is severe or invasive (eg, amebic liver abscess). Likewise eosinophilia is uncommon with parasites residing exclusively in the lumen of the intestinal tract.

The most common parasitic infection in the United States that causes significant eosinophilia with negative stool examination is toxocariasis. Trichinosis, which is a rare parasitic infection in the United States, causes marked eosinophilia. Strongyloidiasis is a cause of eosinophilia that may be difficult to diagnose with stool examinations. The differential diagnosis of eosinophilia is broad for patients who have been in developing countries (see Table 43–2).

SYSTEMIC INFECTIONS

1. Malaria

General Considerations

Malaria causes more than 400,000 deaths each year, over 80% of which occur in children younger than 5 years of age in sub-Saharan Africa and India. Global efforts toward malaria prevention and treatment have led to declining mortality and morbidity. Approximately 2000 imported cases are diagnosed in the United States each year. Human malaria is caused by five Plasmodium species—Plasmodium vivax (most common), Plasmodium falciparum (most virulent), Plasmodium ovale (similar to P vivax), Plasmodium malariae, and Plasmodium knowlesi (a primate parasite now recognized as a cause of falciparum-like malaria in humans).

The female Anopheles mosquito transmits the parasites. Infected mosquitoes inoculate sporozoites into the bloodstream of a susceptible host, resulting in infection of hepatocytes. In the hepatic phase, the parasites mature into schizonts, which rupture and release merozoites into the circulation. These infect and rupture red blood cells in the erythrocytic phase, as they mature from trophozoites to schizonts and release additional merozoites. In early stages of infection, asynchronous erythrocytic cycles of hemolysis commonly cause daily fevers. Eventually if untreated, synchronous erythrocytic cycles may begin as parasites rupture the infected cells at more regular 48- or 72-hour intervals, depending on the infecting species. A small percentage of trophozoites mature into the sexual form (gametocytes) which are taken up in a mosquito blood-meal, thus completing the cycle. Two species, P vivax and P ovale, can remain dormant in liver cells (hypnozoites) leading to recrudescence, months and even years after the acute infection.

Disease severity in malaria is closely linked with prior immunity. Thus, in areas where transmission is stable and frequent, older children and adults will generally develop milder illness with infection, though complete protective immunity rarely occurs. On the other hand, younger children, persons without prior exposure (eg, foreign travelers) or individuals living in areas where transmission is intermittent are at increased risk of severe disease. Additionally, young children, pregnant women, and persons with certain immune dysfunctions (eg, asplenia) are at higher risk of severe disease regardless of prior exposure.

Evidence of the central role malaria has played in human history can be found in the frequency of genetic mutations leading to altered red blood cell phenotypes, including hemoglobin S, hemoglobin F, the thalassemias, possibly glucose-6-phosphate dehydrogenase [G6PD] deficiency, and absent Duffy antigen on red blood cells (which confers protection against P vivax) that may confer partial protection against malaria among populations whose origins are from malaria endemic areas.

Clinical Findings

A. Symptoms and Signs

Clinical manifestations vary according to infecting species and host immunity. The most common manifestations of acute malaria in children include fever, chills, malaise, and headache. Nausea, vomiting, and abdominal pain are common. Infants commonly present with recurrent fever, irritability, poor feeding, vomiting, jaundice, and splenomegaly. Rash is usually absent, which helps distinguish malaria from some viral infections in patients presenting with similar symptoms. In the classic descriptions of malaria, cyclic patterns of fever specific to the infecting species were noted. This finding can take many days to develop and is affected by numerous factors including prior immunity, multiple species infection and treatment, and is rarely useful diagnostically in current practice.

The clinician must be vigilant in monitoring patients with malaria for signs and symptoms of complicated or severe infection, including severe anemia and cerebral malaria, described later.

Infection during pregnancy often causes intrauterine growth restriction or premature delivery, but rarely true fetal infection.

Physical examination in patients with uncomplicated cases may show only mild splenomegaly and mild pallor.

B. Laboratory Findings

Because the manifestations of malaria overlap with a number of other common conditions, the diagnosis should always be confirmed with laboratory testing. The diagnosis relies on detection of one or more of the five human plasmodia in thick and thin blood smears. Three separate sets of thick and thin smears separated by 12–24 hours in a 72-hour period are recommended to rule out malaria infection. Thick smears are most sensitive for detection of small numbers of malaria parasites; thin smears allow identification of species and semiquantitative determination of percentage of parasitemia.

Most acute infections are caused by P vivax, P ovale, or P falciparum, although 5%–7% are due to multiple species. Identification of the Plasmodium species relies on morphologic criteria and requires an experienced observer. Bench aids to assist in the identification of Plasmodium species can be found at http://www.dpd.cdc.gov/dpdx/HTML/Malaria.htm. A U.S. Food and Drug Administration (FDA)-approved antigen detection test is available and approved for rapid diagnostic testing of malaria. This test should be used in conjunction with microscopic examination to confirm diagnosis, look for mixed infection, and quantitate degree of parasitemia. The rapid antigen test has poor sensitivity for low levels of parasitemia. Up-to-date information on rapid diagnostic testing for malaria can be found at www.cdc.gov/malaria/diagnosis_treatment/index.html. Alternative techniques of similar or higher diagnostic accuracy for P falciparum include DNA hybridization and polymerase chain reaction (PCR), which are only available in research and reference laboratories and at CDC and some health departments.

Determining the degree of parasitemia (% of visualized erythrocytes that are infected) from thin smears is important because high levels (> 5%), most often seen in P falciparum malaria, are associated with increased morbidity and mortality and require hospitalization. Measurement over time (12–24 hours) can also be used to monitor treatment responses; the parasite burden should decrease over the first 24–48 hours.

Hemolytic anemia and thrombocytopenia are common; the incidence of leukocytosis is variable. In severe cases, metabolic acidosis, hypoglycemia, and azotemia may occur. The pathogenesis of cerebral malaria is microvascular obstruction. CSF analysis is typically normal.

Differential Diagnosis

Clinical features may not reliably distinguish malaria from other infections in children, so a high index of suspicion in patients with exposure in endemic areas is necessary. The differential diagnosis of fever in a returning traveler should be based on diseases endemic to the region of travel and may include typhoid fever, tuberculosis, rickettsial disease, brucellosis, leptospirosis, yellow fever, dengue fever, chikungunya, and borreliosis. However, other common nontropical causes of fever such as influenza should be considered. Though CSF is typically normal in cerebral malaria, any child with suspected cerebral malaria should undergo lumbar puncture to exclude bacterial meningitis. Malaria may also coexist with other diseases.

Complications & Sequelae

Severe complications, which occur most often in P falciparum and P knowlesi infection, result from hemolysis, microvascular obstruction, and tissue ischemia. The most common complications of malaria in children are cerebral malaria, respiratory distress, severe anemia, and/or hypoglycemia. Cerebral malaria, which is the most serious and life-threatening complication of malaria in children, may progress to seizures, coma, and death. Approximately 20% of children with cerebral malaria die and 10% have long-term neurologic sequelae. Signs of severe malaria in children include altered mental status, seizures, respiratory distress, hypoglycemia, acidosis, end-organ failure, extreme pallor, and parasitemia greater than 5%.

Prevention

There are many strategies to prevent malaria transmission in a community. The most effective is widespread use of bed nets impregnated with long-acting insecticide, because the majority of Anopheles bites occur in evening or night. Mosquito larva control and indoor insecticide spraying are also widespread.

Strategies for personal protection against malaria (particularly for travelers to endemic areas) include use of bed nets, proper clothing, insect repellent, and malaria chemoprophylaxis. The most common medications for malaria prevention in travelers are mefloquine, atovaquone-proguanil, and doxycycline (see Chapter 45). Chloroquine is of limited utility due to widespread resistance. Factors impacting decisions regarding choice of medication include cost, side effects, drug interactions, and epidemiology and resistance patterns in the planned travel area. Specific requirements for starting medication before travel and continuing for a certain duration after travel depend on the medication.

No drug regimen guarantees protection against malaria. If fever develops within 1 year (particularly within 2 months) after travel to an endemic area, the possibility of malaria should be considered.

Treatment

Choice of antimalarial treatment depends on the immune status of the person, plasmodium species, degree of parasitemia, and resistance patterns in the geographical region of acquisition. A description of the recommended antimalarial drugs available in the United States with updated treatment guidelines is available at https://www.cdc.gov/malaria/diagnosis_treatment/treatment.html. Atovaquone/proguanil and the artemisinin combination artemether/lumefantrine are first-line therapies for uncomplicated malaria in the United States. For severe malaria, intravenous artesunate is superior to quinidine and can result in rapid reduction in parasitemia, but must always be followed by an oral combination drug when the patient improves in order to prevent resistance. IV artesunate is available under an expanded access investigational new drug protocol through the CDC. Common treatments for infections with P vivax and P ovale include chloroquine plus either primaquine or the recently approved tafenoquine, which can eradicate liver stage malaria with a single dose. The CDC provides 24-hour telephone malaria hotline consultation for providers at (770) 488-7788.

Treatment for malaria includes a variety of supportive strategies in addition to the antimalarial drugs. It is advisable to hospitalize nonimmune patients infected with P falciparum and P knowlesi until a decrease in parasitemia is demonstrated, indicating that treatment is effective and severe complications are unlikely to occur. Patients with signs of severe malaria (parasitemia > 5%, cerebral malaria, acidosis, hypoglycemia, shock) require intensive care and parenteral treatment. Hydration and treatment of hypoglycemia are of utmost importance. Anemia, seizures, pulmonary edema, and renal failure require conventional supportive management. Corticosteroids are contraindicated for cerebral malaria because of increased mortality. Exchange transfusion is no longer recommended for the treatment of severe malaria.

Partially immune patients with uncomplicated P falciparum and P knowlesi infection and nonimmune persons infected with P vivax, P ovale, or P malariae can receive outpatient treatment if follow-up is reliable.

2. Babesiosis

Babesia microti is a malaria-like protozoan that infects humans bitten by infected nymphal-stage Ixodes scapularis (deer tick). After inoculation, the protozoan penetrates erythrocytes and starts an asynchronous cycle that causes hemolysis. In the United States, the majority of cases occur in the Northeast and upper Midwest from May to October. Babesia infection is also a transfusion-transmissible disease.

Clinical Findings

A. Symptoms and Signs

The incubation period is 1–4 weeks after tick bite, or 1–9 weeks after blood transfusion. The tick bite may go unnoticed as Ixodes nymphs are about the size of a poppy seed. Approximately half of infected children are asymptomatic. Symptoms are nonspecific and most commonly include sustained or cyclic high fever, rigors, and sweats. Other associated nonspecific symptoms include malaise, fatigue, anorexia, arthralgias, myalgias, and headache. Physical examination findings are usually minimal, but may include hepatosplenomegaly, jaundice, or dark urine. The disease is usually self-limited, causing symptoms for 1–2 weeks with fatigue that may persist for months. Severe cases have been described in asplenic patients, immunocompromised hosts, and elderly patients with comorbidities. Because Babesia, Borrelia burgdorferi, and Anaplasma phagocytophilum share a common vector, physicians should consider the possibility of coinfection in patients diagnosed with any of these pathogens.

B. Laboratory Findings

Anemia, thrombocytopenia, and evidence of renal insufficiency may be noted. Definitive diagnosis is made by identifying babesial parasites in blood by microscopic evaluation of thin or thick blood smears or by PCR amplification of babesial DNA in blood samples. Babesia parasites are intraerythrocytic organisms that resemble P falciparum ring forms. The tetrad form (Maltese cross), if visualized, is pathognomonic. Specific serologic tests are also available through the CDC.

Treatment

Azithromycin (10 mg/kg up to 500 mg on the first day, followed by 5 mg/kg up to 250 mg/day) in combination with atovaquone (20 mg/kg, up to 750 mg, twice a day) for 7–10 days is the treatment of choice for mild-to-moderate disease. For severely ill patients, clindamycin (10 mg/kg, up to 600 mg, every 8 hours) in combination with quinine (8 mg/kg, up to 650 mg, every 8 hours) is standard of care. Longer courses of treatment may be needed in immunocompromised patients. Partial or complete RBC exchange transfusion is indicated for persons with severe babesiosis, as indicated by high-grade parasitemia (≥ 10%); significant hemolysis; or renal, hepatic, or pulmonary compromise.

3. Toxoplasmosis

General Considerations

T gondii is a worldwide parasite of animals and birds. Felines, the definitive hosts, excrete oocysts in their feces. Ingested mature oocysts or tissue cysts lead to tachyzoite invasion of intestinal cells. Intracellular replication of the tachyzoites causes cell lysis and spread of the infection to adjacent cells or to other tissues via the bloodstream. In chronic infection, T gondii appears as bradyzoite-containing tissue cysts that do not trigger an inflammatory reaction. In immunocompromised hosts, tachyzoites are released from cysts and begin a new cycle of infection.

The two major routes of Toxoplasma transmission to humans are oral and congenital. Oral infection occurs after ingestion of cysts from food, water, or soil contaminated with cat feces or from ingestion of undercooked meat or other food products that contain cysts. Oocysts survive up to 18 months in moist soil but survival is limited in dry, very cold, or very hot conditions and at high altitude, which probably accounts for the lower incidence of toxoplasmosis in these climatic regions. In the United States, less than 1% of cattle and 25% of sheep and pigs are infected with toxoplasmosis. In humans, depending on geographic area, seropositivity increases with age from 0% to 10% in children younger than 10 years to 3%–70% in adults.

Congenital transmission occurs during acute infection of pregnant women. Rarely, fetal infection has been documented in immunocompromised mothers who have chronic toxoplasmosis. Treatment during pregnancy decreases transmission by 60%.

Clinical Findings

Clinical toxoplasmosis can be divided into four groups: (1) congenital infection, (2) infection acquired in the immunocompetent host, (3) infection acquired or reactivated in the immunocompromised host, and (4) ocular disease.

A. Congenital Toxoplasmosis

Congenital toxoplasmosis, which is the result of acute infection during pregnancy, occurs in 1 in 3000–10,000 live births in the United States. The rate of transmission and disease severity in the baby vary according to when in pregnancy the infection is acquired. First-trimester infections lead to congenital infections about 10%–20% of the time. Clinical disease that occurs at this time can be severe, with microcephaly or hydrocephaly, severe chorioretinitis, hearing loss, convulsions, abnormal cerebrospinal fluid (CSF) (xanthochromia and mononuclear pleocytosis), cerebral calcifications, and intellectual disability. Other findings include strabismus, maculopapular rash, pneumonitis, myocarditis, hepatosplenomegaly, jaundice, thrombocytopenia, lymphocytosis and monocytosis, and an erythroblastosis-like syndrome. Infection of a mother in the third trimester results in a 70%–90% rate of congenital infection, but most of these children are asymptomatic at birth, although they remain at risk of subsequent ocular disease and subtle neurologic deficits.

B. Acquired Toxoplasma Infection in the Immunocompetent Host

Typically, acquired infection in the immunocompetent host is asymptomatic. About 10%–20% of patients develop an infectious mononucleosis-like syndrome with lymphadenopathy and/or a flu-like illness. Affected nodes are discrete, variably tender, and do not suppurate. Cervical lymph nodes are most frequently involved, but any nodes may be enlarged. Less common findings include fever, malaise, myalgias, fatigue, hepatosplenomegaly, lymphopenia (usually < 10%), and liver enzyme elevations. Unilateral chorioretinitis may occur. Recovery typically occurs without any specific antiparasitic treatment, although lymph node enlargement may persist or wax and wane for a few months to 1 or more years. Animal and epidemiologic studies have suggested an association between toxoplasmosis infection and behavioral changes and mental illness (particularly schizophrenia) but these associations remain unproven.

C. Acute Toxoplasmosis in the Immunodeficient Host

Patients infected with human immunodeficiency virus (HIV), and those with lymphoma, leukemia, or transplantation, are at high risk for developing severe disease (most commonly central nervous system disease, but also chorioretinitis, myocarditis, or pneumonitis) following acute infection or reactivation. Toxoplasmic encephalitis is a common cause of mass lesions in the brains of persons with HIV/AIDS.

D. Ocular Toxoplasmosis

Ocular toxoplasmosis is an important cause of chorioretinitis in the United States. In children, it results most often from reactivation of congenital infection but can also follow acquired infection. Congenitally infected individuals are usually asymptomatic until the second or third decade of life when symptomatic eye disease occurs due to the rupture of tissue cysts and the release of bradyzoites and tachyzoites into the retina. Typically, ocular toxoplasmosis presents as a focal necrotizing retinochoroiditis often associated with a preexistent chorioretinal scar, and variable involvement of the vitreous, retinal blood vessels, optic nerve, and anterior segment of the eye.

E. Diagnostic Findings

Serologic tests are the primary means of diagnosis, but results must be interpreted carefully, particularly in the evaluation of congenital toxoplasmosis. Active infection can also be diagnosed by PCR of blood or body fluids; by visualization of tachyzoites in histologic sections or cytology preparations, cysts in placenta or fetal tissues; or by characteristic lymph node histology. IgG antibodies become detectable 1–2 weeks after infection, peak at 1–2 months, and thereafter persist for life. IgM antibodies appear earlier and decline faster than IgG antibodies, but can last for 12–18 months after acute infection. Isolated IgM antibodies with negative IgG, should not be interpreted as positive due to poor specificity. A single positive titer determination is nondiagnostic; IgG seroconversion or a fourfold increase in titer from paired samples drawn at least 3 weeks apart are diagnostic in the right clinical scenario. Absence of both serum IgG and IgM in an immunocompetent individual virtually rules out the diagnosis of toxoplasmosis. In the immunocompromised host, serologic tests are not sensitive, and active infection is documented by PCR or finding tachyzoites by histologic examination.

The diagnosis of toxoplasmosis in the older child with visual complaints is usually made by finding T gondii IgG or IgM antibodies in the serum in the presence of a typical eye lesion. The diagnosis can be confirmed by detecting T gondii DNA by PCR in the aqueous humor, though this is rarely performed.

Congenital infection is confirmed by histologic or molecular identification of trophozoites in amniotic fluid, placenta, or infant tissue. Infant blood, CSF, and amniotic fluid specimens should be assayed by PCR. More often, diagnosis is established using a combination of serologic testing of mother and baby and clinical findings. Evaluation of a newborn should include Toxoplasma-specific IgG, IgM, IgA, and IgE of the newborn and mother in coordination with an experienced reference lab. A congenital infection is confirmed serologically by detecting persistent or increasing IgG antibody levels compared to the mother, persistently positive IgG antibodies beyond the first year of life, and/or a positive T gondii-specific IgM or IgA antibody test in the infant. In addition, the child should have thorough ophthalmologic, auditory, and neurologic evaluation; a lumbar puncture; and computed tomographic (CT) scan of the head (to detect CNS calcifications).

Differential Diagnosis

Congenital toxoplasmosis must be differentiated from infection with cytomegalovirus, rubella, herpes simplex, and syphilis. Acquired infection in immune competent host can mimic infectious mononucleosis, as well as viral, bacterial, or lymphoproliferative disorders. Ocular toxoplasmosis can mimic other infectious, noninfectious, and neoplastic ocular conditions.

Prevention

Primary prevention of toxoplasmosis in pregnant women (and immunocompromised patients) is an essential public health goal. Effective strategies to prevent food-borne transmission of toxoplasmosis include adequate cooking or prolonged precooking freezing of meats; washing of fruits, vegetables, and cooking surfaces; and avoidance of unpasteurized goat milk and uncooked crustaceans (oysters, clams, mussels), particularly during pregnancy. Exposure to potential environmental sources can be minimized by using gloves when gardening/handling soil that may have been contaminated by cat feces, covering sandboxes, and good hygiene. Pregnant women should not purchase a new kitten and avoid changing cat litter; if unavoidable, gloves and hand-hygiene are essential and litter should be changed regularly because oocysts require 48–72 hours to sporulate and become infectious. Though maternal treatment can prevent congenital transmission, implementation of serologic screening of pregnant women is challenging.

Treatment

The most common medications to treat toxoplasmosis are pyrimethamine (given with leucovorin to limit bone marrow toxicity) and sulfadiazine. Acute toxoplasmosis in the immunocompetent host does not require specific therapy, unless the infection occurs during pregnancy. In primary maternal infection during the first 18 weeks of pregnancy, spiramycin is recommended to attempt to prevent fetal infection. Spiramycin does not cross the placenta, so does not treat fetal infection once established. If fetal infection has been documented or if primary maternal infection occurs after the first 18 weeks of pregnancy, pyrimethamine, sulfadiazine, and leucovorin are recommended. Pyrimethamine is teratogenic and should not be used before 18 weeks of gestation.

Treatment of toxoplasmic chorioretinitis consists of oral pyrimethamine (2 mg/kg maximum, 200 mg loading dose followed by 1 mg/kg daily [maximum 75 mg]) plus sulfadiazine (100 mg/kg daily, maximum 1500 mg), given with leucovorin (10–20 mg three times a week). In addition, corticosteroids (prednisone 1 mg/kg daily) are given when lesions threaten vision. The duration of additional therapy should be guided by frequent ophthalmologic examinations. Pyrimethamine can cause gastrointestinal upset, leukopenia, thrombocytopenia, and rarely, agranulocytosis; weekly complete blood counts should be checked while on therapy.

A year of treatment is recommended for all congenitally infected infants. Children treated with pyrimethamine (loading dose 2 mg/kg daily for 2 days followed by 1 mg/kg daily for 6 months followed by 1 mg/kg every Monday, Wednesday, and Friday for 6 months) plus sulfadiazine (100 mg/kg divided twice daily for 12 months) plus leucovorin (10 mg three times a week) have better neurodevelopmental and visual outcomes than historical controls. While on therapy, infants should be monitored for bone marrow toxicity.

GASTROINTESTINAL INFECTIONS

1. Amebiasis

General Considerations

Infection with Entamoeba histolytica occurs worldwide, but has a particularly high prevalence in areas with poor sanitation and socioeconomic conditions. In the United States, most infections are seen in travelers to, and emigrants from, endemic areas, but can occur without travel exposure. The majority of infections are asymptomatic (> 90%), but tissue invasion can result in amebic colitis, hepatic abscess, and hematogenous spread to other organs. Transmission is usually fecal-oral. Two Entamoeba species, E dispar and E moshkovskii, are morphologically indistinguishable from E histolytica and are much more commonly encountered in stool samples. Infections with these species are cause minimal (E moshkovskii) or no human disease (E dispar). Molecular techniques are likely to identify additional species in the future (eg, E bangladeshi).

Clinical Findings

A. Symptoms and Signs

Patients with intestinal amebiasis can have asymptomatic cyst passage (> 90%), or be symptomatic with acute amebic proctocolitis, chronic nondysenteric colitis, or ameboma. Patients with acute amebic colitis typically have a 1- to 2-week history of loose stools containing blood and mucus, abdominal pain, and tenesmus. A minority of patients are febrile or dehydrated. Abdominal examination may reveal pain over the lower abdomen.

Fulminant colitis is an unusual complication of amebic dysentery that is associated with a grave prognosis (> 50% mortality), and is characterized by severe bloody diarrhea, fever, and diffuse abdominal pain. Children younger than age 2 years are at increased risk for this condition. Chronic amebic colitis causes recurrent episodes of bloody diarrhea over a period of years and is clinically indistinguishable from idiopathic inflammatory bowel disease. An ameboma is a localized amebic infection, usually in the cecum or ascending colon, which presents as a painful abdominal mass.

The most common complications of intestinal amebiasis are intestinal perforation, toxic megacolon, and peritonitis. Perianal ulcers, a less common complication, are painful, punched-out lesions that usually respond to medical therapy. Infrequently, colonic strictures may develop following colitis.

Patients with amebic liver abscess, the most common form of extraintestinal amebiasis, typically present with acute fever and right upper quadrant tenderness. The pain may be dull, pleuritic, or referred to the right shoulder. Physical examination reveals liver enlargement in fewer than 50% of affected patients. Some patients have a subacute presentation lasting 2 weeks to 6 months. In these patients, hepatomegaly, anemia, and weight loss are common findings, and fever is less common. Jaundice and diarrhea are rarely associated with an amebic liver abscess. In children with fever of unknown origin who live in, or travel to, endemic areas, amebic liver abscess should be considered in the differential diagnosis.

The most common complication of amebic liver abscess is pleuropulmonary amebiasis due to rupture of a right liver lobe abscess. Lung abscesses may occur from hematogenous spread. Cough, dyspnea, and pleuritic pain can be caused by the serous pleural effusions and atelectasis that frequently accompany amebic liver abscesses. Rupture of hepatic abscesses can lead to peritonitis and more rarely to pericarditis. Amebic brain or spinal cord abscess is an infrequent manifestation.

B. Diagnostic Findings

The differential diagnosis of acute amebic colitis includes bacterial (eg, Salmonella spp, Shigella spp, E coli spp, Campylobacter spp), parasitic (eg, Balantidium coli), and noninfectious (eg, inflammatory bowel disease, diverticulitis, ischemic colitis) causes of dysentery. Chronic amebic colitis has to be distinguished from inflammatory bowel disease and Cyclospora. Amebic liver abscess must be distinguished from an echinococcal hydatid cyst and abscesses caused by typical enteric bacteria. Occult blood is present in virtually all cases of amebic colitis and can be used as an inexpensive screening test. Fecal leukocytes are uncommon.

Intestinal amebiasis has been traditionally diagnosed by detecting the parasite on stool examination or mucosal biopsy. However, E histolytica is morphologically identical to nonpathogenic E dispar and E moshkovskii, and the majority of amebas diagnosed by microscopy are not E histolytica and cannot be easily differentiated by microscopy. Stool antigen detection tests are very sensitive and specific for E histolytica. Increasingly, diagnosis is confirmed using PCR, often in the context of a multiplex stool pathogen panel. Though these assays appear sensitive and specific for E histolytica, identification of multiple pathogens in a stool sample can present challenges in determining the actual cause of diarrhea. Colonoscopy and biopsy are most helpful when stool studies are nondiagnostic and other intestinal pathology (eg, Crohn’s) are possible. Barium studies are contraindicated for patients with suspected acute amebic colitis due to risk of perforation.

Because extra-intestinal manifestations of E histolitica infection most commonly occur in individuals with negative stool testing, diagnosis in these settings often relies on serum specific antibody detection. ELISA assays are positive in approximately 95% of patients with extraintestinal amebiasis, 70% with intestinal E histolytica disease, and 10% of asymptomatic patients shedding E histolytica cysts. However, these antibodies persist for years, and a positive result does not distinguish between acute and past infection. Ultrasonographic examination and CT, which are sensitive techniques to detect hepatic abscesses, can be used to guide fine-needle aspiration to obtain specimens for definitive diagnosis. The classic appearance of drainage from a hepatic amebic abscess is described as “anchovy paste.”

Prevention & Treatment

Travelers to endemic areas should drink bottled or boiled water and eat cooked or peeled vegetables and fruits to prevent enteric infection.

Treatment of amebic infection is complex because different agents are required for eradicating the parasite from the bowel or tissue (Table 43–3). Whether treatment of asymptomatic cyst passers is indicated is controversial. The prevalent opinion is that confirmed asymptomatic infection with E histolytica should be treated in nonendemic areas.

Asymptomatic E histolytica cyst excreters may be treated with paromomycin, a nonabsorbable intraluminal amebicide. Metronidazole is not effective against cysts.

Patients with symptomatic intestinal amebiasis or extraintestinal disease require treatment with an absorbable agent, such as metronidazole or tinidazole, followed by an intraluminal agent, even if the stool examination is negative. Tinidazole is a more effective treatment than metronidazole and is well tolerated in children. Metronidazole and paromomycin should not be given concurrently, because the diarrhea that is a common side effect of paromomycin may make it difficult to assess response to therapy. In most patients with amebic liver abscess, aspiration is unnecessary and does not speed recovery. Patients with large, thin-walled hepatic abscesses may need therapeutic aspiration to avoid abscess rupture. Drainage may also be considered when response to medical therapy is inadequate.

2. Giardiasis

General Considerations

Giardiasis, caused by Giardia intestinalis, is the most common intestinal protozoal infection in children in the United States and in most of the world. The infection is classically associated with drinking contaminated water, either in rural areas or in areas with faulty purification systems. Even ostensibly clean urban water supplies and pristine mountain streams can be contaminated intermittently, and infection has been acquired in swimming pools. Fecal-oral contamination allows person-to-person spread. Day care centers are a major source of infection. Food-borne outbreaks also occur. Giardiasis may occur at any age, although infection is rare in neonates. High rates of transmission occur among men who have sex with men. Domestic animals are rarely sources of human infection due to strain differences between humans and pets.

Clinical Findings

A. Symptoms and Signs

Giardia infection results in either asymptomatic cyst passage, acute self-limited diarrhea, or a chronic syndrome of diarrhea, malabsorption, and weight loss. Acute diarrhea occurs 1–2 weeks after infection and is characterized by abrupt onset of diarrhea with greasy, malodorous stools, malaise, flatulence, bloating, and nausea. Fever and vomiting are unusual. The disease has a protracted course (> 1 week) and frequently leads to weight loss. Patients who develop chronic diarrhea complain of profound malaise, lassitude, headache, and diffuse abdominal pain in association with bouts of diarrhea—most typically foul-smelling, greasy stools—intercalated with periods of constipation or normal bowel habits. This syndrome can persist for months until specific therapy is administered or until it subsides spontaneously. Chronic diarrhea frequently leads to malabsorption, steatorrhea, micronutrient deficiencies, and disaccharidase depletion. Lactose intolerance, which develops in 20%–40% of patients can persist for several weeks after treatment, and needs to be differentiated from relapsing giardiasis or reinfection.

B. Laboratory Findings

Increasingly, the diagnosis of giardiasis in the United States is made by stool PCR, often in the context of a multiplex stool pathogen panel. Though these assays appear sensitive and specific for Giardia, identification of multiple pathogens in a stool sample can present challenges in determining the actual cause of diarrhea, particularly in patients exposed in poor income countries where carriage of Giardia is extremely common. Alternative methods of diagnosis include Giardia antigen detection by means of ELISAs, nonenzymatic immunoassays, and direct fluorescence antibody tests. In areas without access to PCR or antigen tests, the diagnosis of giardiasis can be made by finding the parasite in stool. For O&P examination, a fresh stool provides the best results. Liquid stools have the highest yield of mobile trophozoites, which are more readily identified on wet mounts. With semiformed stools or those that cannot immediately be examined, the examiner should look for cysts in fresh or fixed specimens, preferably using a concentration technique.

Prevention

The prevention of giardiasis requires proper treatment of water supplies and interruption of person-to-person transmission. Where water might be contaminated, travelers, campers, and hikers should use methods to make water safe for drinking. Boiling is the most reliable method; the necessary time of boiling (1–3 minute at sea level) will depend on the altitude. Chemical disinfection with iodine or chlorine and filtration are alternative methods of water treatment.

Interrupting fecal-oral transmission requires strict hand washing. However, outbreaks of diarrhea in day care centers might be particularly difficult to eradicate. Reinforcing hand washing and treating the disease in both symptomatic and asymptomatic carriers may be necessary.

Treatment

Metronidazole, tinidazole, and nitazoxanide are the traditional drugs of choice for treatment of giardiasis. A recent meta-analysis concluded that single dose tinidazole (50 mg/kg; max 2 g) should be the preferred treatment based on both better efficacy and convenience compared to other treatments. There are fewer data on the use of tinidazole in children under 3 years. When given at 5 mg/kg (up to 250 mg) three times a day for 5–7 days, metronidazole has 80%–95% efficacy. Nitazoxanide (100 mg [5 mL] every 12 hours for children 12–47 months of age, 200 mg every 12 hours for 4- to 11-year-olds, and 500 mg every 12 hours for children 12 years or older) is available in liquid formulation and requires only 3 days of treatment. For patients who do not respond to therapy or are reinfected, a second course with the same drug or switching to another drug is equally effective. In cases of repeated treatment failure paromomycin or albendazole may be effective.

3. Cryptosporidiosis

The intracellular protozoa Cryptosporidia are the leading cause of recreational water-associated diarrheal outbreaks in the United States. Cryptosporidia may also cause severe and devastating diarrhea in patients with untreated acquired immunodeficiency syndrome (AIDS) and in other immunodeficient persons. This ubiquitous parasite infects and reproduces in the epithelial cell lining of the digestive and respiratory tracts of humans and most other vertebrate animals. Humans acquire the infection from contaminated drinking water, recreation water sources (including swimming pools, fountains, and lake water), or from close contact with infected humans or animals. Petting zoos and day care centers have been other sources of Cryptosporidia outbreaks. Most human infections are caused by C parvum or C hominis.

Clinical Findings

A. Symptoms and Signs

Immunocompetent persons infected with Cryptosporidium usually develop self-limited diarrhea (2–26 days) with or without abdominal cramps. Diarrhea can be mild and intermittent or continuous, watery, and voluminous. Low-grade fever, nausea, vomiting, loss of appetite, and malaise may accompany the diarrhea. Children younger than 2 years are more susceptible to infection than older children. Immunocompromised patients (either cellular or humoral deficiency) tend to develop a severe, prolonged, chronic diarrhea which, despite treatment, can result in severe malnutrition and subside only after the immunodeficiency is corrected. Other clinical manifestations associated with cryptosporidiosis in immunocompromised hosts include cholecystitis, pancreatitis, hepatitis, biliary tree involvement, and respiratory symptoms.

B. Laboratory Findings

Though visualization of Cryptosporidia oocysts in concentrated stool samples is diagnostic, PCR—often in the context of a multiplex stool pathogen panel—is rapidly replacing diagnostic microscopy, and is highly sensitive and specific. Alternate tests include direct immunofluorescent antibody (DFA) of stool.

Prevention & Treatment

Prevention of Cryptosporidium infection is limited by oocyst resistance to some of the standard water purification procedures (including chlorine) and common disinfectants. Enteric precautions are recommended for infected persons. Boiled or bottled drinking water may be considered for patients at high risk for developing chronic infection (eg, inadequately treated patients with AIDS). Infected persons should avoid swimming pools.

Many infections in immunocompetent individuals are self-limited, thus treatment is supportive and primarily directed at prevention of dehydration. Severe of prolonged cases in immunocompetent patients and some patients with immunodeficiencies respond to treatment with nitazoxanide, antidiarrheal agents, and hydration. Immunocompromised patients usually require more intense supportive care with parenteral nutrition in addition to hydration and nonspecific antidiarrheal agents. Recommended doses of nitazoxanide are 100 mg (5 mL) every 12 hours for children 12–47 months of age, 200 mg every 12 hours for 4–11 year olds, and 500 mg every 12 hours for children 12 years or older. For patients with advanced AIDS, antiparasitic therapy alone has not proven efficacious. Institution of effective antiretroviral therapy results in elimination of symptomatic cryptosporidiosis.

4. Cyclosporiasis

Cyclospora spp are ubiquitous coccidian parasites that infect humans and a variety of animals worldwide. Cyclospora cayetanensis is the only species known to infect humans. Cyclosporiasis is seen in three main epidemiologic settings: sporadic cases in endemic areas, travelers to endemic areas, and in food- or water-borne outbreaks in nonendemic areas, particularly in relation to importation of fresh produce. The incubation period is approximately 7 days (range 2–14 days). Infection may be asymptomatic, cause mild-to-moderate self-limited diarrhea, or cause protracted or severe diarrhea. In the immunocompetent host, diarrhea usually lasts 10–25 days but may be followed by a relapsing pattern that can last several months. Diarrhea is frequent, watery, sometimes explosive, and often accompanied by nausea, vomiting, abdominal cramping, and bloating. Profound fatigue, anorexia, and myalgia have been reported. The infection can be unusually severe in immunocompromised patients, especially those with inadequately treated HIV/AIDS. Although the illness is self-limited, it may last for several weeks in the absence of treatment. Diagnosis is based on finding oocysts 8–10 mm in diameter on examination of stool specimens stained with acid-fast stain. PCR of stool is available at the CDC and some reference laboratories. Treatment is trimethoprim-sulfamethoxazole for 7 days; no other medication has proven effective.

5. Free-Living Amebas

General Considerations

Infections with free-living amoebas are uncommon. Naegleria species, Acanthamoeba species, and Balamuthia amoebas have been associated with human disease, primarily infections of the central nervous system.

Acute meningoencephalitis, caused by Naegleria fowleri, occurs mostly in children and young adults. Patients present with abrupt fever, headache, nausea, and vomiting, disturbances in smell and taste, meningismus, and decreased mental status a few days to 2 weeks after exposure. Infection is often associated with swimming in warm freshwater lakes and using contaminated tap water for nasal irrigation. CNS invasion occurs after nasal inoculation of N fowleri which travel along the olfactory nerves via the cribiform plate to the brain. The disease is rapidly progressive and nearly universally fatal within a week of symptom onset.

Chronic granulomatous encephalitis, caused by Acanthamoeba or Balamuthia, can occur in immunocompetent patients, but occurs more commonly in immunocompromised patients. There is no association with freshwater swimming. This disease has an insidious onset of focal neurologic deficits, and approximately 50% of patients present with headache. Skin, sinus, or lung infections with Acanthamoeba precede many of the CNS infections and may still be present at the onset of neurologic disease. Granulomatous encephalitis progresses to fatal outcome over a period of weeks to months (average 6 weeks).

Acanthamoeba keratitis is a corneal infection associated with minor trauma or use of soft contact lenses in otherwise healthy persons. Clinical findings of Acanthamoeba keratitis include radial keratoneuritis and stromal ring infiltrate. Amebic keratitis usually follows an indolent course and initially may resemble herpes simplex or bacterial keratitis; delay in diagnosis is associated with worse outcomes.

Clinical Findings & Differential Diagnosis

Amebic encephalitis should be included in the differential diagnosis of acute meningoencephalitis in children with a history of recent freshwater swimming. The CSF is usually hemorrhagic, with leukocyte counts that may be normal early in the disease but later range from 400 to 2600/mL with neutrophil predominance, low to normal glucose, and elevated protein. The etiologic diagnosis relies on finding trophozoites on a wet mount of the CSF. Immunofluorescent and PCR-based diagnostic assays are available through the CDC.

Granulomatous encephalitis is diagnosed by brain biopsy of CT-identified nonenhancing lucent areas. The CSF of these patients is usually nondiagnostic with a lymphocytic pleocytosis, mild to severe elevation of protein (> 1000 mg/dL), and normal or low glucose. Acanthamoeba and Balamuthia amoebas have only rarely been found in the CSF; however, they can be visualized in brain biopsies or grown from brain or other infected tissues. Immunofluorescent and PCR-based diagnostic assays are available through the CDC.

Acanthamoeba keratitis is diagnosed by finding the trophozoites in corneal scrapings or by isolating the parasite from corneal specimens or contact lens cultures.

Prevention

Because primary amebic meningitis occurs infrequently, active surveillance of lakes for N fowleri is not warranted. However, in the presence of a documented case, it is advisable to close the implicated lake to swimming. Sterile or boiled water should be used for nasal irrigation. Acanthamoeba keratitis can be prevented by heat disinfection of contact lenses, storage of lenses in sterile solutions, use of disposable daily lenses, and by not wearing lenses when swimming in freshwater or showering.

Treatment

Treatment of amebic encephalitis is complex and frequently unsuccessful. Urgent consultation with the CDC is recommended for all cases (CDC Emergency Operations Center at 770-488-7100). Though treatment numbers are small, regimens containing miltefosine (an antiparasitic used for treatment of leishmania) may increase survival in Balamuthia mandrillaris and Acanthamoeba infections. A recent case demonstrated successful treatment of a 9-year-old with Naegleria meningoencephalitis using miltefosine in combination with amphotericin B, fluconazole, rifampin, azithromycin, dexamethasone, and whole-body cooling to 34°C.

Acanthamoeba keratitis responds well to surgical debridement followed by 3–4 weeks of topical 1% miconazole; 0.1% propamidine isethionate; and polymyxin B sulfate, neomycin, and bacitracin (Neosporin).

TRICHOMONIASIS

Trichomonas vaginalis infection is discussed in Chapter 44.

NEMATODE INFECTIONS

1. Enterobiasis (Pinworms)

General Considerations

This worldwide infection is caused by Enterobius vermicularis. The adult worms are about 5–10 mm long and live in the colon; females deposit eggs on the perianal area, primarily at night, which cause intense pruritus. Scratching contaminates the fingers and allows transmission back to the host (autoinfection) or to contacts through fecal-oral spread.

Clinical Findings

A. Symptoms and Signs

Pinworms are associated with intense localized pruritis of the anus and vulva. Adult worms may migrate within the colon or up the urethra or vagina in girls. They can be found within the bowel wall, in the lumen of the appendix (usually an incidental finding by the pathologist), in the bladder, and even in the peritoneal cavity of girls.

B. Laboratory Findings

The usual diagnostic test consists of pressing a piece of transparent tape on the child’s anus in the morning prior to bathing, then placing it on a drop of xylene on a slide. Microscopic examination under low power usually demonstrates the ova. Scrapings from under fingernails may also be positive. Parents may visualize adult worms in the perianal region, often at nighttime while the child is asleep. Though stool testing for pinworm is typically negative, incidental identification of the flagellate parasite Dientamoeba fragilis in a stool O&P examination may suggest the presence of Enterobius, though the relationship between these two organisms is incompletely understood.

Differential Diagnosis

Nonspecific irritation or vaginitis, streptococcal perianal cellulitis (usually painful with marked erythema), and vaginal or urinary bacterial infections may at times resemble pin-worm infection, although the symptoms of pinworms are often so suggestive that a therapeutic trial is justified without a confirmed diagnosis.

Treatment

A. Specific Measures

Treat all household members at the same time to prevent reinfections. Because the drugs are not active against the eggs, therapy should be repeated after 2 weeks to kill the recently hatched adults. Significant constipation may impair treatment responses.

Pyrantel pamoate, available without a prescription, is given as a single dose (11 mg/kg; maximum 1 g); it is safe, inexpensive and very effective. Albendazole (400 or 200 mg in children 1–2 years of age) in a single dose is also highly effective for all ages (though not approved by the US FDA). Ivermectin is also effective against pinworm.

B. General Measures

Personal hygiene must be emphasized. Nails should be kept short and clean. Children should wear undergarments in bed to diminish contamination of fingers; bedclothes should be laundered frequently; infected persons should bathe in the morning, thereby removing a large proportion of eggs.

2. Ascariasis

General Considerations

The whipworm, hookworms (see later), and Ascaris comprise the “soil-transmitted helminths.” These parasites cause human infection through contact with eggs or larvae that thrive in the moist soil of the tropics and subtropics. Worldwide, more than a billion people are infected with at least one of these parasites, and, especially in less developed countries, it is not uncommon for children to be chronically and repeatedly infected with multiple worms. These parasites are strongly associated with poverty and lack of clean water and sanitation. Children infected with these worms are at increased risk for malnutrition, stunted growth, intellectual disability, and cognitive and education deficits. Together, the soil-transmitted helminths are one of the world’s most important causes of physical and intellectual impairment, with the majority of this burden falling on children.

Ascaris lumbricoides is a worldwide human parasite. Ova passed by carriers may remain viable for months under the proper soil conditions. The ova contaminate food or fingers and are subsequently ingested by a new host. The larvae hatch, penetrate the intestinal wall, enter the venous system, reach the alveoli, are coughed up the trachea and swallowed, returning to the small intestine, where they mature. The female lays thousands of eggs daily.

Clinical Findings

A. Symptoms and Signs

The majority of infections with A lumbricoides are asymptomatic, although moderate to heavy infections are associated with abdominal pain, weight loss, anorexia, diarrhea, and vomiting, and may lead to malnutrition. During the larval migratory phase, an acute transient eosinophilic pneumonitis (Löffler syndrome) may occur. Acute intestinal obstruction has been associated with heavy infections, which is more common in children due to their smaller intestinal diameter and higher worm burden. Worm migration can cause appendicitis, common bile duct obstruction (resulting in biliary colic, cholangitis, or pancreatitis), or peritonitis.

B. Laboratory Findings

The diagnosis is made by observing the large roundworms (15–40 cm) in the stool or by microscopic detection of the ova on concentrated stool examination.

Treatment

Ascaris is treated with albendazole (400 mg in a single dose, or 200 mg in children 1–2 years of age), mebendazole (100 mg twice a day for 3 days or 500 mg once), and ivermectin (150–200 mcg/kg orally once). Nitazoxizide is also effective. In cases of intestinal or biliary obstruction, piperazine (150 mg/kg initially, followed by six doses of 65 mg/kg every 12 hours by nasogastric tube) can be used to paralyze the worms and help relieve obstruction. However, surgical removal is occasionally required. Because reinfection is common in areas of high worm burden, regular deworming programs are employed to mitigate chronic nutritional and development impacts on children, though results have been disappointing in the setting of rapid reinfection.

3. Trichuriasis (Whipworm)

Trichuris trichiura is a widespread human and animal parasite common in children living in warm, humid areas conducive to survival of the ova, and is one of the soil-transmitted helminths of major global health significance. Ingested infectious eggs hatch in the upper small intestine. The adult worms live in the cecum and colon; the ova are passed and become infectious after several weeks in the soil. Unlike Ascaris, Trichuris does not have a migratory tissue phase. Symptoms are not present unless the infection is severe, in which case pain, diarrhea, iron-deficiency anemia, and mild abdominal distention are present. Massive infections may also cause rectal prolapse and dysentery. Detection of the characteristic barrel-shaped ova in the feces confirms the diagnosis. Adult worms may be seen in the prolapsed rectum or at proctoscopy; their thin heads are buried in the mucosa, and the thicker posterior portions protrude. Mild-to-moderate eosinophilia may be present.

Treatment with mebendazole (100 mg orally twice a day for 3 days) or albendazole (400 mg in a single dose for 3 days, or 200 mg in children 1–2 years of age) tends to improve gastrointestinal symptoms when present. Combination therapy involving more than one drug may be more effective than single-drug therapy for refractory cases.

4. Hookworm

General Considerations

The common human hookworms are Ancylostoma duodenale and Necator americanus. Both are widespread in the tropics and subtropics, with an estimated 600–700 million people infected worldwide. The larger A duodenale is more pathogenic because it consumes more blood, up to 0.5 mL per worm per day.

The adults live in the jejunum. Eggs are passed in the feces and develop and hatch into infectious in warm, damp soil within 2 weeks. The larvae penetrate human skin on contact, enter the blood, reach the alveoli, are coughed up and swallowed, and develop into adults in the intestine. The adult worms attach to intestinal mucosa, from which they suck blood. Blood loss is the major sequela of infection; protein loss due to bleeding and disruption of the mucosal surface may also occur. Infection rates reach 90% in areas without sanitation.

Ancylostoma braziliense and Ancylostoma caninum (the dog and cat hookworm) cause cutaneous larva migrans, a creeping skin eruption in children and others who come in contact with soil contaminated with cat and dog feces. In the United States, the disease is most prevalent in the Southeast, but most cases are imported by travelers returning from tropical and subtropical areas.

Clinical Findings

A. Symptoms and Signs

Patients with hookworm infection usually are asymptomatic. Chronic hookworm infection leads to blood loss and iron-deficiency anemia. Heavy infection can cause hypoproteinemia with edema. Chronic hookworm infection in children may lead to growth delay, deficits in cognition, and developmental delay. The larvae usually penetrate the skin of the feet and cause a stinging or burning sensation, followed by an intense local itching (ground itch) and a papulovesicular rash that may persist for 1–2 weeks. Pneumonitis associated with migrating larvae is uncommon and usually mild, except during heavy infections. Colicky abdominal pain, nausea, and/or diarrhea and marked eosinophilia may be observed.

In cutaneous larva migrans, larvae produce pruritic, reddish papules at the site of skin entry and intensely pruritic, serpiginous tracks or bullae appear as they migrate through the skin, which is pathognomonic for this disease. Larvae can move up to a few centimeters a day and activity can continue for several weeks, but eventually the rash is self-limiting.

B. Laboratory Findings

The large ova of both species of hookworm are found in feces and are indistinguishable. Microcytic anemia, hypoalbuminemia, eosinophilia, and hematochezia occur in severe cases.

Prevention

Avoiding fecal contamination of soil and avoiding barefoot skin contact with potentially contaminated soil is recommended.

Treatment

A. Specific Measures

Albendazole (400 mg orally in a single dose, or 200 mg in children 1–2 years of age) is significantly more efficacious than mebendazole or pyrantel pamoate and is considered the drug of choice for treatment of hookworm infections.

B. General Measures

Iron therapy and vitamin A supplementation in conjunction with deworming programs may help mitigate some of the negative nutritional and micronutrient effects of infection with hookworm and the other soil-transmitted helminths, particularly in settings where reinfection occurs rapidly.

5. Strongyloidiasis

General Considerations

Strongyloides stercoralis is unique in having both parasitic and free-living forms; the latter can survive in the soil for prolonged periods. The parasite is found in most tropical and subtropical regions of the world, including some areas of the southeastern United States. The adults live in the submucosal tissue of the duodenum and occasionally elsewhere in the intestines. Eggs deposited in the mucosa hatch rapidly and thus the first-stage (rhabditiform) larvae are the predominant form found in duodenal aspirates and feces, rather than eggs. The larvae mature rapidly to the tissue-penetrating filariform stage and initiate internal autoinfection within the intestine or in the perianal area. The filariform larvae passed in stool to the environment persist in soil and can penetrate the skin of another host, subsequently migrating into veins and pulmonary alveoli, reaching the intestine when coughed up and swallowed.

Older children and adults are infected more often than are young children. Immunosuppressed patients may develop fatal disseminated strongyloidiasis, known as the hyperinfection syndrome. Autoinfection can result in persistent infection for decades.

Clinical Findings

A. Symptoms and Signs

Chronic S stercoralis infections can be asymptomatic or cause cutaneous, gastrointestinal, and/or pulmonary symptoms. At the site of skin penetration, a pruritic rash may occur. Autoinfection from larvae present in stool may result in severe itching in the perianal area and a rapidly migrating rash called larva currens. Migrating larvae in the lungs can cause wheezing, cough, shortness of breath, and hemoptysis. Although intestinal infections are often asymptomatic, the most prominent features of clinical strongyloidiasis include abdominal pain, distention, diarrhea, vomiting, and occasionally malabsorption.

Patients with cellular immunodeficiencies and those on corticosteroids or chemotherapy may develop disseminated infection, sometimes many years after the last exposure (eg, in immigrants living for prolonged periods in the United States), involving the intestine, the lungs, and the meninges. Gram-negative sepsis may complicate disseminated strongyloidiasis.

B. Laboratory Findings

A marked eosinophilia is common in strongyloidiasis. Definitive diagnosis can be difficult because of low parasite load and irregular larval output in stool; a minimum of three stool samples should be examined. Finding larvae (not eggs) in the feces, duodenal aspirates, or sputum is diagnostic. IgG antibodies measured by ELISA or immunoblot are relatively sensitive (83%–93%). The presence of specific antibody does not distinguish between past and present infection. However, because prolonged, minimally symptomatic infections frequently occur, a person with a positive IgG test and no history of treatment should be considered infected. Strongyloides antibody assays can cross-react with other helminth infections. Patients with pulmonary symptoms with suspected Strongyloides infection should have sputum samples evaluated for the detection of S stercoralis in addition to antibody testing.

Differential Diagnosis

Strongyloidiasis should be differentiated from peptic disease, celiac disease, regional or tuberculous enteritis, and hookworm infections. The pulmonary phase may mimic asthma or bronchopneumonia. Patients with severe infection can present with an acute abdomen.

Prevention & Treatment

Ivermectin (two doses of 0.2 mg/kg given 1–14 days apart) is the drug of choice. Albendazole is an alternative treatment but appears to have lower efficacy. Relapses are common. In the hyperinfection syndrome, 1–3 weeks of therapy with ivermectin may be necessary and multiple follow-up stool studies for 2 weeks after therapy are indicated to ensure clearance of larvae. Patients from endemic areas should be serotested and treated at the time of immigration or before undergoing immunosuppression, including short courses of corticosteroid therapy for conditions such as asthma.

6. Visceral Larva Migrans (Toxocariasis)

General Considerations

Visceral larva migrans is a worldwide disease including all areas of the United States. The agent is the cosmopolitan intestinal ascarid of dogs and cats, Toxocara canis or Toxocara cati. The eggs passed by infected animals contaminate parks and other areas that young children frequent. Children with pica are at increased risk. In the United States, seropositivity ranges from 2.8% in unselected populations to 23% in southern states to 54% in rural areas. Ingested eggs hatch and penetrate the intestinal wall, then migrate to the liver. Most of the larvae are retained in the liver, but some may pass through the organ reaching the lungs, eyes, muscles, and/or the CNS, where they die and incite a granulomatous inflammatory reaction.

Clinical Findings

A. Visceral Larva Migrans

Toxocariasis is usually asymptomatic, but young children (aged 1–5 years) sometimes present with anorexia, fever, fatigue, pallor, abdominal pain and distention, nausea, vomiting, and cough. Hepatomegaly is common, splenomegaly is unusual, and adenopathy is absent. Lung involvement, usually asymptomatic, can be demonstrated readily by radiologic examination. Seizures are common, but more severe neurologic abnormalities are infrequent. IgG antibody detection by ELISA is sensitive, specific, and useful in confirming the clinical diagnosis. Most patients recover spontaneously, but disease may last up to 6 months.

B. Ocular Larva Migrans

This condition occurs in older children and adults who present with a unilateral posterior or peripheral inflammatory eye mass. History of visceral larva migrans and eosinophilia are typically absent. Anti-toxocara antibody titers are low in the serum but may be elevated in vitreous and aqueous fluids.

C. Diagnostic Findings

Leukocytosis with marked eosinophilia, anemia, and elevated liver function tests are typical. Hypergammaglobulinemia may be present. The diagnosis can be confirmed by finding larvae in granulomatous lesions. More often, positive serology and the exclusion of other causes of hypereosinophilia provide a presumptive diagnosis in typical cases.

Differential Diagnosis

Diseases associated with hypereosinophilia must be considered. Other parasitic infections include trichinosis (enlarged liver not common; muscle tenderness common), Baylisascaris (racoon roundworm, also encountered in US children), Ascaris, and strongyloides. Noninfectious causes of significant eosinophilia in children include allergies and drug hypersensitivity syndromes, and rarely eosinophilic leukemia and collagen-vascular disease.

Prevention & Treatment

A. Specific Measures

Treatment with albendazole (400 mg twice a day for 5 days) or mebendazole (100–200 mg twice a day for 5 days) is recommended for visceral infection. Aggressive anti-inflammatory treatment with systemic corticosteroids should accompany anti-parasitic treatment for ocular larva migrans.

B. General Measures

Treating any cause of pica, such as iron deficiency, is important. Corticosteroids are used to treat marked inflammation of lungs, eyes, or other organs. Pets should be dewormed routinely.

7. Trichinosis

General Considerations

Trichinella are small roundworms that infest hogs and several other meat-eating animals. Currently, there are eight recognized Trichinella species, of which Trichinella spiralis is the most common human pathogen, and most adapted to domestic and wild swine. The most important source of human infection worldwide is the domestic pig. Cases and outbreaks have been associated with numerous game animals, particularly wild boar and bear, but also wild felines, fox, horse, seal, and walrus. The human cycle begins with ingestion of viable larvae in undercooked meat. In the small intestine, the larvae develop into adult worms that mate and produce larvae, which enter the bloodstream and migrate to the striated muscle where they continue to grow and eventually encyst. Symptoms are caused by the inflammatory response in the intestines or muscle.

Clinical Findings

A. Symptoms and Signs

Most infections are asymptomatic. The severity of clinical disease is strongly correlated with the number of ingested larvae. Infection can be divided into two phases: an intestinal phase (typically within 1–2 days of cyst ingestion) and a muscular or systemic phase (typically 2 weeks after infection). The initial bowel penetration may cause fever, headache, chills, and abdominal pain, nausea, vomiting, and diarrhea within 1 week after ingestion of contaminated meat. This may progress to the classic myopathic form, which consists of fever, eyelid or facial edema, myalgia, and weakness. Other signs may include maculopapular exanthem, subungual bleeding, conjunctivitis and subconjunctival hemorrhages, headaches, dry cough, and painful movement of the eye muscles. Rare complications include myocarditis, thromboembolic disease, and encephalitis. Severe cerebral involvement or myocarditis can be fatal. Symptoms usually peak after 2–3 weeks but may last for months. Children typically have milder clinical and laboratory findings than adults.

B. Diagnosis

The diagnosis of trichinosis is suggested by the constellation of typical clinical findings (fever; myalgias; eyelid and/or facial edema; gastrointestinal symptoms and subconjunctival, subungual, and retinal hemorrhages), history of potential exposure (particularly to wild game or undercooked pork), and nonspecific laboratory findings (particularly marked eosinophilia, elevated muscle enzymes). Confirmation can be challenging, and depends primarily on demonstration of Trichinella-specific IgG antibody. Sensitivity and specificity of serologic testing may be enhanced by serial testing to demonstrate a rise in titer. Muscle biopsy may demonstrate encysted larvae, which are diagnostic.

Differential Diagnosis

Manifestations of the intestinal phase of trichinosis are similar to many acute gastrointestinal infections; obtaining a history of recent dietary exposure to a potential source of Trichinella is essential if the diagnosis is to be considered at this stage. The systemic phase may mimic the fever and myalgias of influenza. The classic symptoms are pathognomonic if one is aware of this disease. Facial swelling may mimic complicated sinusitis. Marked eosinophilia is seen in toxocariasis, strongyloidiasis, and schistosomiasis (travel history).

Prevention

Because a microscopic examination must be performed, meat in the United States is not inspected for trichinosis. Although all states require the cooking of hog swill, hog-to-hog or hog-to-rat cycles may continue. All pork and sylvatic meat (eg, bear or walrus) should be cooked at least > 160°F followed by a 3 minute rest. Freezing meat to at least 5°F for 3 weeks may also prevent transmission. Animals used for food should not be fed or allowed access to raw meat. Careful cleaning and disinfection of meat-grinding equipment is essential, particularly after processing of wild game.

Treatment

Albendazole (400 mg twice daily for 8–14 days) is the drug of choice for trichinosis. Concurrent corticosteroids (prednisone 30–60 mg/day for 10–15 days) are used for treatment of severe symptoms. Administration of analgesics is sometimes required. Relapses occur, particularly when treatment occurs late in the myopathic stage.

Prognosis

Prognosis for severe cases with cardiac and cerebral complications is poor, with a mortality rate around 5%. In milder cases, prognosis is good, and most patients’ symptoms disappear within 2–6 months.

8. Raccoon Roundworm Infections

General Considerations

Human infections with Baylisascaris procyonis, the raccoon roundworm, though rare, may result in a severe and potentially fatal illness. Humans who ingest the eggs excreted in raccoon feces become accidental hosts when the larvae penetrate the gut and disseminate via the bloodstream to the brain, eyes, viscera, and muscles. Pica and exposure to raccoon latrines (location of communal raccoon defecation) represent the main risk factors. Most infections are asymptomatic, but cases of severe encephalitis (neural larva migrans), endophthalmitis (ocular larva migrans), and visceral larva migrans may occur. Symptoms typically begin 2–4 weeks after inoculation. CNS infections present as acute, rapidly progressive encephalitis with eosinophilic pleocytosis of the CSF (varies from 4% to 68% eosinophils in mild pleocytosis). Death or severe neurologic injuries are common. Both CNS and ocular infections resemble other larva migrans infections such as toxocariasis; therefore, B procyonis should be considered in the differential diagnosis of these infections when Toxocara serology is negative. The diagnosis of B procyonis is established by observing the larvae on examination of tissue biopsies or by serology (of serum or CSF), and should be considered in the differential diagnosis in anyone with CSF eosinophilia. Antihelmintic drugs have not been shown to have any beneficial effect for the treatment of baylisascariasis, since they lack larvicidal effects in human tissues. Nevertheless, albendazole (20–40 mg/kg/day for 1–4 weeks) has been used to treat most cases, together with anti-inflammatory drugs. Complete resolution of symptoms has not been achieved thus far. Immediate prophylactic treatment with albendazole (25 mg/kg daily for 20 days) should be considered for those with known ingestion of raccoon feces.

CESTODE INFECTIONS (FLUKES)

1. Taeniasis & Cysticercosis

General Considerations

Cysticercosis affects as many as 100 million people globally, and is the leading cause of seizures in many developing countries. In the United States, cases are most often noted in individuals who have resided in Latin America. Pigs are the usual intermediate host of the tapeworm Taenia solium. Human cysticercosis occurs when the eggs, which are excreted in the feces of a human infected with the parasite, are ingested. Importantly, cysticercosis cannot be acquired by eating pork; rather, ingestion of pork may result in adult tapeworm infection (taeniasis) because infected pork contains the larval cysts that develop into the adult tapeworm but does not contain the eggs which cause cysticercosis. It is possible for an individual with taeniasis to auto-ingest eggs from their own intestinal tapeworm, and thus develop cysticercosis.

Larvae released from ingested eggs enter the circulation to encyst in a variety of tissues, especially muscle and brain (neurocysticercosis). Full larval maturation occurs in 2 months, but the cysts cause little inflammation until the larvae die months to years later. Inflammatory edema ensues with calcification or disappearance of the cyst. A slowly expanding mass of sterile cysts at the base of the brain may cause obstructive hydrocephalus (racemose cysticercosis).

T solium and the beef tapeworm (Taenia saginata), which can causes taeniasis but not cysticercosis, are distributed worldwide. Contamination of foods by eggs in human feces allows person-to-person spread without travel to endemic areas.

Clinical Findings

A. Symptoms and Signs

1. Taeniasis

In most tapeworm infections, the only clinical manifestation is the passage of fecal proglottids, which are white, motile segments of tapeworm 1–2 cm in size. In contrast to the soil transmitted helminths (hookworms, ascaris) tapeworms are not associated with significant nutritional deficiencies. Children may harbor the adult worm for years and complain of abdominal pain, anorexia, and diarrhea. As they are often longer (up to 30 feet) T saginata may cause more symptoms than T solium.

2. Cysticercosis

In the parenchymatous form, the parasite lodges in tissue as a single or multiple cysts. Granuloma formation results with eventual pericystic inflammation, which is the cause of seizures in most patients. The initial stage of the cyst is viable, where the scolex exists within the cyst and there is minimal or no enhancement due to a limited host immune response. As the scolex dies, either due to the host immune response or cysticidal treatment there is a strong immune response, characterized by enhancement on CT or MRI. As the cyst further degenerates, it calcifies, leading to punctuate calcifications on CT scan. Brain cysts may remain silent or cause seizures, headache, hydrocephalus, and basilar meningitis. Rarely, the spinal cord is involved. Neurocysticercosis manifests an average of 5 years after exposure, but may cause symptoms in the first year of life. In the eyes, cysts cause bleeding, retinal detachment, and uveitis. Definitive diagnosis requires histologic demonstration of larvae or cyst membrane. Presumptive diagnosis is often made by the characteristics of the cysts seen on CT scan or MRI. The presence of T solium eggs in feces is uncommon with cysticercosis (see above) but can support the diagnosis.

B. Laboratory Findings

Neuroimaging is the mainstay of diagnosis of neurocysticercosis. The diagnosis should be suspected in any patient who has lived in an endemic area and presents with a compatible clinical picture and suggestive lesions on neuroimaging. In endemic areas it is not uncommon for lesions of cysticercosis to be noted incidentally on neuroimaging performed for other reasons (eg, trauma).

Eggs or proglottids may be found in feces or on the perianal skin (using the tape method employed for pinworms). Eggs of both Taenia species are identical. The species are identified by examination of proglottids.

Peripheral eosinophilia is minimal or absent. CSF eosinophilia is seen in 10%–75% of cases of neurocysticercosis; its presence supports an otherwise presumptive diagnosis.

Antibody testing of serum and CSF can strongly support the diagnosis when neuroimaging is abnormal. Titers are eventually positive in up to 98% of serum specimens and over 75% of CSF specimens from patients with neurocysticercosis. Solitary cysts are associated with seropositivity less often than are multiple cysts. High titers tend to correlate with more severe disease or more numerous encysted lesions. CSF titers are higher if cysts are near the meninges.

The differential diagnosis of neurocysticercosis includes tuberculous granuloma, microabscesses, arachnoid cyst, neoplasms, and vascular lesions.

Treatment

A. Taeniasis

Oral praziquantel (5–10 mg/kg once) or niclosamide (50 mg/kg once, maximum 2 g) can be used for treatment of tapeworm carriers.

B. Cysticercosis

The treatment modalities for neurocysticercosis include cysticidal agents (to kill larvae), corticosteroids (to decrease or prevent the inflammatory reaction), antiepileptic drugs (to control seizures if present), and surgery (to remove cysts or for placement of a shunt for hydrocephalus). Most experts would recommend treatment with a cysticidal agent in most cases of neurocysticercosis, except in patients with inactive, calcified lesions. In patients with viable parenchymal cysts, cysticidal therapy decreases the burden of parasites and the number of seizures. Similarly, cysticidal therapy is associated with more complete and faster resolution on imaging and fewer seizures in patients with a single, small enhancing lesion. Ophthalmic examination should be conducted prior to cysticidal therapy to rule out intraocular cysts.

Albendazole, 15 mg/kg/day (maximum, 800 mg) divided in two doses daily for 8–15 days, is the treatment of choice. Larval death may result in clinical worsening because of inflammatory edema. A concurrent course of dexamethasone (0.1 mg/kg/day to a maximum of 6 mg/day) or prednisolone (1 mg/kg/day to a maximum of 40–60 mg) is recommended to decrease these symptoms. Corticosteroids are mandatory treatment for large intraventricular cysts and encephalitis (dexamethasone 0.1 mg/kg/day or prednisolone 1 mg/kg/day for as long as needed). Giant subarachnoidal cysts may require more than one cycle of therapy or surgery (or both). Minimally invasive neurosurgery (neuroendoscopic extraction) is the currently recommended management of intraventricular cysts. Follow-up scans every several months help assess the response to therapy.

Prevention

Prevention of taeniasis requires proper cooking of meat. Neurocysticercosis is prevented by careful washing of raw vegetables and fruits, treating intestinal carriers, avoiding the use of human excrement for fertilizer, and providing proper sanitary facilities.

Prognosis

The prognosis is good in intestinal taeniasis. Symptoms associated with a few cerebral cysts may disappear in a few months; heavy brain infections may cause death or chronic neurologic impairment. Seizures may persist even in those patients with only calcified lesions and anticonvulsants may be needed indefinitely.

2. Hymenolepiasis

Hymenolepis nana, or dwarf tapeworm, is a common parasite of children; Hymenolepis diminuta, the rat tapeworm, is rare. The former is capable of causing autoinfection. Larvae hatched from ingested eggs penetrate the intestinal wall and then reenter the lumen to mature into adults. Their eggs are immediately infectious for the same or a new host. The adult is only a few centimeters long. Finding the characteristic eggs in feces is diagnostic.

H diminuta has an intermediate stage in rat fleas and other insects; children are infected when they ingest these insects.

Light infections with either tapeworm are usually asymptomatic; heavy infection can cause diarrhea and abdominal pain. Therapy is with praziquantel (25 mg/kg once).

3. Echinococcosis

General Considerations

Two species of Echinococcus can cause disease in humans, E granulosus and E multilocularis. The two forms of echinococcus, cystic and alveolar, cause significant morbidity and mortality worldwide; cystic echinococcus is endemic in many areas of the developing world, and alveolar echinococcus is typically found in far norther latitudes. Dogs and other canids are the definitive host for E granulosis and become infected through ingestion of infected organs of numerous herbivorous animals (especially sheep, but also goats, swine, horses, cattle, and camels) which serve as intermediate hosts. For E multilocularis, foxes are the principle definitive hosts and rodents are the intermediate hosts. Human infection occurs following incidental ingestion of eggs in canid stool. When ingested by humans, the eggs hatch, and the larvae penetrate the intestinal mucosa and disseminate via the bloodstream to produce cysts; the primary sites of involvement are the liver (60%–70%) and the lungs (20%–25%). A unilocular cyst is most common. Over time, the cyst may reach 25 cm in diameter, although most are much smaller. The cysts of Echinococcus multilocularis are multilocular and demonstrate more rapid growth.

Clinical Findings

A. Symptoms and Signs

The clinical manifestations of echinococcosis are variable and depend primarily on the site, size, and condition of the cysts. The rates of growth of cysts are variable, and range between 1 and 5 cm in diameter per year. In cystic echinococcus, a slowly growing single cyst often goes unnoticed until it causes dysfunction due to its size. Hepatomegaly, right upper quadrant pain, nausea, and vomiting may occur. If a cyst ruptures, the sudden release of its contents can result in a severe allergic reaction. Cysts may cause biliary obstruction. Most hepatic cysts are in the right lobe. Alveolar echinococcus typically involves lung, and is characterized by a tumor-like lesion that can invade, necrose, and metastasize.

Rupture of a pulmonary cyst causes coughing, dyspnea, wheezing, urticaria, chest pain, and hemoptysis; cyst and worm remnants are found in sputum. Brain cysts may cause focal neurologic signs and convulsions; renal cysts cause pain and hematuria; bone cysts cause pain.

B. Laboratory Findings

Antibody assays are useful to support the diagnosis following identification of a cystic lesion on imaging, and currently available ELISA tests have high sensitivity. Immunoblot assays and direct parasitologic examination can confirm the presence of echinococcus from aspirated or resected samples. Eosinophilia is present in only about 25% of patients. Abnormal liver enzymes may suggest biliary obstruction.

C. Imaging

The presence of a cyst-like mass in a person with appropriate epidemiologic exposure supports the diagnosis. Visualization of daughter cysts (cysts within a larger cyst) is highly suggestive of echinococcosis. CT, MRI, and ultrasonography are useful for the diagnosis of deep-seated lesions. Abdominal ultrasonography is the most widely used diagnostic tool. Pulmonary or bone cysts may be visible on plain films.

Differential Diagnosis

Tumors, bacterial or amebic abscess, cavitary pulmonary tuberculosis, mycoses, and benign cysts must be considered.

Complications

Sudden cyst rupture with anaphylaxis and death is the worst complication. If the patient survives, secondary infections from seeding of daughter cysts may occur. Segmental lung collapse, secondary bacterial infections, effects of increased intracranial pressure, and severe liver or renal damage due to cysts are other potential complications.

Treatment

There is no “best” treatment option for cystic echinococcus, and no clinical trial has compared all the different treatment modalities. Definitive therapy of E multilocularis requires meticulous surgical removal of the cysts. A surgeon familiar with this disease should be consulted. Albendazole chemotherapy should be initiated for several days prior to surgery. Chemotherapy alone cures about one-third of patients. Albendazole (15 mg/kg/day divided in two doses for 3 months, max 400 mg twice daily), sometimes with the addition of praziquantel, is the regimen of choice. A third treatment option is a four-step procedure (PAIR: puncture, aspiration, injection, and reaspiration). This procedure consists of (1) percutaneous puncture using ultrasound guidance, (2) aspiration of liquid contents, (3) injection of a protoscolicidal agents (95% ethanol or hypertonic saline for at least 15 minutes), and (4) reaspiration. PAIR is indicated for uncomplicated cases, or those not amenable to surgery. If the cyst leaks or ruptures during surgical or percutaneous drainage a severe, potentially life-threatening allergic reaction may occur. For alveolar echinococcus, radical surgery for complete resection of the cyst is the goal. In some patients (particularly in whom complete resection is not possible), lifetime chemotherapy may be required.

Prognosis

Patients with large liver cysts may be asymptomatic for years. Surgery is often curative for lung and liver cysts, but not always for cysts in other locations.

TREMATODE INFECTIONS

Schistosomiasis

General Considerations

One of the most common serious parasitic diseases, schistosomiasis, is caused by several species of Schistosoma flukes. Schistosoma japonicum, Schistosoma mekongi, and Schistosoma mansoni involve the intestines, and Schistosoma haematobium involves the urinary tract. The first two species are found in eastern and southeastern Asia; S mansoni in tropical Africa, the Caribbean, and parts of South America; and S haematobium in Africa. Important transmission sites include Lake Malawi and Lake Victoria in Africa, Poyang and Dongting Lakes in China, and along the Mekong River in Laos.

Infection is caused by free-swimming larvae (cercariae), which emerge from the intermediate hosts that are certain species of freshwater snails. The cercariae penetrate human skin, migrate to the liver, and mature into adults, which then migrate through the portal vein to lodge in the bladder veins (S haematobium), superior mesenteric veins (S mekongi and S japonicum), or inferior mesenteric veins (S mansoni). Clinical disease results primarily from inflammation caused by the many eggs that are laid in the perivascular tissues or that embolize to the liver. Escape of ova into bowel or bladder lumen allows microscopic visualization and diagnosis from stool or urine specimens, as well as contamination of freshwater and infection of the snail hosts that ingest them.

Clinical Findings

Much of the population in endemic areas is infected but asymptomatic. Only heavy infections produce symptoms.

A. Symptoms and Signs

Schistosomiasis progresses in three distinct phases: acute, chronic, and advanced disease. The cercarial penetration may cause a maculopapular, pruritic rash, comprising discrete, erythematous, raised lesions that vary in size from 1 to 3 cm. The symptoms of acute schistosomiasis (Katayama syndrome) can last from days to weeks, and can include fever, malaise, cough, diarrhea, hematuria, and right upper quadrant pain. The chronic stages of gastrointestinal disease are characterized by hepatic fibrosis, portal hypertension, splenomegaly, ascites, and bleeding from esophageal varices. The chronic stages of genitourinary tract disease may result in obstructive uropathy, stones, infection, bladder cancer, fistulas, and anemia due to chronic hematuria. Terminal hematuria in children from an endemic region is a red flag for urinary schistosomiasis. Spinal cord granulomas and paraplegia due to egg embolization into the Batson plexus have been reported.

B. Laboratory Findings

The diagnosis is made by finding the species-specific eggs in feces (S japonicum, S mekongi, S mansoni, and occasionally S haematobium) or urine (S haematobium and occasionally S mansoni). If no eggs are found, concentration methods should be used. Because the shedding of eggs can vary, three specimens should be obtained. Urine specimens should be collected between 10 AM and 2 PM to coincide with the timing of maximal egg secretion. Testing should wait until 2 months after the last known freshwater contact as this is the time required for worms to start producing eggs following infection. Serological tests are also useful, especially for making the diagnosis in patients who are not excreting eggs. Peripheral eosinophilia is common, and eosinophils may be seen in urine.

Prevention

The best prevention is to avoid contact with contaminated freshwater in endemic areas. Efforts to destroy the snail hosts have been successful in areas of accelerated economic development.

Treatment

A. Specific Measures

Praziquantel is the treatment of choice for schistosomiasis. A dosage of 40 mg/kg/day in two divided doses (S mansoni or S haematobium) over 1 day or 20 mg/kg three times a day (S japonicum or S mekongi) over 1 day is very effective and nontoxic. Praziquantel has no effect on eggs and immature worms and therefore a repeat dose 4–6 weeks later is sometimes needed.

B. General Measures

The patient’s urinary tract should be evaluated carefully in S haematobium infection; reconstructive surgery may be needed. Hepatic fibrosis requires careful evaluation of the portal venous system and surgical management of portal hypertension when appropriate.

Prognosis

Therapy decreases the worm burden and liver size, despite continued exposure in endemic areas. Early disease responds well to therapy, but once significant scarring or severe inflammation has occurred, eradication of the parasites is of little benefit.

Fungi can be classified as yeasts, which are unicellular and reproduce by budding; as molds, which are multicellular and consist of tubular structures (hyphae) and grow by elongation and branching; or as dimorphic fungi, which can exist either as yeasts or molds depending on environmental conditions. Categorization according to anatomic and epidemiologic features is shown in Table 43–4. Fungal cells are taxonomically distinct from plant and animal cells. These differences, especially cell wall and cell membrane components, are utilized for diagnosis and are the basis of specific therapy.

In the United States, systemic fungal disease in normal hosts is commonly caused by three endemic organisms—Coccidioides, Histoplasma, and Blastomyces—which are restricted to certain geographic areas. Prior residence in or travel to these areas, even for a brief time, is a prerequisite for inclusion in a differential diagnosis. Of these three, Histoplasma most often relapses years later in patients who are immunosuppressed.

Immunosuppression (especially depressed T-cell–mediated immunity), foreign bodies (eg, urinary and central catheters for Candida), ulceration of gastrointestinal and respiratory mucosa, severe burns, broad-spectrum antimicrobial therapy, malnutrition, HIV infection, and neutropenia or neutrophil defects are major risk factors for fungal infections (termed “opportunistic fungal infections”).

Laboratory diagnosis may be difficult because of the small number of fungi present in some lesions, slow growth of some organisms, and difficulty in distinguishing normal colonization of mucosal surfaces from infection. A tissue biopsy with fungal stains and culture is the best method for diagnosing some systemic fungal disease. Repeat blood cultures may be negative even in the presence of intravascular infections. Serologic tests are useful for diagnosing coccidioidomycosis and histoplasmosis, and antigen detection in urine and blood is useful for diagnosing blastomycosis, histoplasmosis, cryptococcosis, and aspergillosis.

The common superficial fungal infections of the hair and skin are discussed in Chapter 15.

Blastomycosis

General Considerations

The causative fungus, Blastomyces dermatitidis, is found in soil primarily in the Mississippi and Ohio River valleys, additional southeastern and south central states, and the states bordering the Great Lakes. Transmission is by inhalation of spores. Subclinical disease is common. Infection rates are similar in both sexes in children, but severe disease is much more common in adults and males.

Clinical Findings

A. Symptoms and Signs

Primary infection is often unrecognized (> 50%). Clinical disease typically includes cough with purulent sputum, chest pain, headache, weight loss, night sweats, and fever. These occur several weeks to months after inoculation. Infection is most often self-limited in immunocompetent patients, but in some patients an indolent progressive pulmonary disease occurs after an incubation period of 20–100 (median 45) days. Cutaneous lesions (20% of patients) usually represent disseminated disease. Skin lesions are slowly progressive and become ulcers with a sharp, heaped-up border or develop a verrucous appearance. Bone disease resembles other forms of chronic osteomyelitis. Lytic skull lesions in children are typical, but long bones, vertebrae, and the pelvis may be involved. Extrapulmonary disease occurs in 25%–40% of patients with progressive disease. A total body radiographic examination is advisable when blastomycosis is diagnosed in the skin or other extrapulmonary site.

B. Laboratory Findings

An initial suppurative response is followed by an increase in mononuclear cells and subsequent formation of noncaseating granulomas. Diagnosis requires isolation or visualization of the fungus. Pulmonary specimens (sputum, tracheal aspirates, or lung biopsy) may be positive using conventional or fungal cell wall stains. The budding yeasts have refractile thick walls and are very large and distinctive (figure-of-eight appearance). The fungus can be readily isolated in most laboratories, but a week is often required. Sputum specimens are positive in more than 80% of cases and in almost all bronchial washings, and skin lesions are positive in 80%–100%. Antibody tests are generally not helpful for diagnosis, but an ELISA antigen detection method, similar to that used for histoplasmosis, readily detects Blastomyces antigen in serum, urine, and lung lavage fluids. In this assay, there is cross-reactivity with histoplamosis. Methods based on detecting blastomyces DNA are now available.

C. Imaging

Radiographic lobar consolidation and fibronodular interstitial and patchy alveolar infiltrates are typical in cases with progressive pneumonia; effusions, hilar nodes, and cavities are less common. The paucity of cavitation and absence of hilar adenopathy distinguishes acute blastomycosis from histoplasmosis and tuberculosis. Miliary patterns also occur with acute infection. Chronic disease can develop in the upper lobes, with cavities and fibronodular infiltrations similar to those seen in tuberculosis. However, unlike tuberculosis or histoplasmosis, these lesions rarely caseate or calcify.

Differential Diagnosis

Primary pulmonary infection resembles acute viral, bacterial, or mycoplasmal infections and is generally confused with atypical community-acquired pneumonia. Blastomycosis should be considered when a significant pulmonary infection in an endemic area fails to respond to antibiotic therapy. Subacute infection mimics tuberculosis, histoplasmosis, and coccidioidomycosis. Chronic pulmonary or disseminated disease must be differentiated from cancer, tuberculosis, or other fungal infections.

Treatment

One view is that all children with proven blastomyces should receive antifungal therapy. Certainly any patient who is symptomatic at the time of diagnosis with moderately severe or life-threatening blastomycosis (especially if immunocompromised), or has CNS infection, should have therapy initiated with the lipid formulation of amphotericin B (3–5 mg/kg intravenously) for 1–2 weeks or until improved. This is followed by oral itraconazole (5–10 mg/kg/day; divided into two doses [maximum = 400 mg]) for 6 months. Mild-to-moderate blastomycosis is often treated with oral itraconazole alone for 6–12 months. Bone disease may require a full year of itraconazole therapy. Surgical debridement is required for devitalized bone, drainage of large abscesses, and pulmonary lesions not responding to medical therapy.

Prognosis

Treatment with at least 1 g of amphotericin results in 75%–90% clearance without relapse. Patients initially treated with itraconazole have a 95% cure rate.

Candidiasis

General Considerations

Disease due to Candida is caused by C albicans in greater than 50% of cases in children; severe systemic infection may also be caused by C tropicalis, C parapsilosis, C glabrata, C krusei, and a few other Candida species. Infections with C auris have become a major global health threat. C auris is frequently highly drug-resistant and has been associated with several outbreaks in health care settings. Speciation is important because of differences in pathogenicity and response to antifungal therapy.

C albicans is ubiquitous, usually in small numbers, on skin, mucous membranes, or in the intestinal tract. Normal bacterial flora, intact epithelial barriers, neutrophils, and macrophages, in conjunction with antibody and complement and normal lymphocyte function, are factors in preventing invasion. Disseminated infection is almost always preceded by prolonged broad-spectrum antibiotic therapy, instrumentation (including intravascular catheters), and/or immunosuppression. Patients with diabetes mellitus are prone to superficial Candida infection; thrush and vaginitis are most common. Candida is the fourth most common blood isolate in hospitals in the United States and is a common cause of catheter-related urinary tract infection.

Clinical Findings

A. Symptoms and Signs

1. Oral candidiasis (Thrush)

Adherent creamy white plaques on the buccal, gingival, or lingual mucosa are seen. These may be painful. Lesions may be few and asymptomatic, or they may be extensive, extending into the esophagus. Thrush is very common in otherwise normal infants in the first weeks of life and may last weeks despite topical therapy. Spontaneous thrush in older children is unusual unless they have recently received antimicrobials. Corticosteroid inhalation for asthma predisposes patients to thrush. HIV infection or other immune deficiency should be considered if there is no other reason for oral thrush, especially when it is persistent or recurrent. Angular cheilitis is the name given to painful erythematous fissures caused by Candida at the corners of the mouth, occasionally in association with vitamin or iron deficiencies.

2. Vaginal infection

Vulvovaginitis occurs in sexually active girls, in diabetic patients, and in girls receiving antibiotics. Oral contraception and pregnancy are risk factors. Thick, odorless, cheesy discharge with intense pruritus is typical. The vagina and labia are usually erythematous and swollen. Outbreaks are more frequent before menses.

3. Skin infection

Diaper dermatitis is often due entirely or partly to Candida. Pronounced erythema with a sharply defined margin and satellite lesions is typical. Pustules, vesicles, papules, or scales may be seen. Weeping, eroded lesions with a scalloped border are common. Any moist area, such as axillae, under breasts, and inguinal or neck folds, may be involved.

Such findings in immunocompromised patients may represent cutaneous dissemination.

These conditions occur in immunocompetent children but more commonly with immunosuppression, hypoparathyroidism, or adrenal insufficiency (Candida endocrinopathy syndrome). The selective absence of specific innate and T-cell responses to Candida can lead to marked, chronic skin and nail infections called chronic mucocutaneous candidiasis.

This may occur in patients who have received multiple courses of antibiotics and are superinfected with Candida.

4. Enteric infection

Esophageal involvement in immunocompromised patients is the most common enteric manifestation, resulting in substernal pain, dysphagia, and painful swallowing. Nausea and vomiting are common in young children. Most patients do not have thrush. Stomach or intestinal ulcers also occur. Candidal peritonitis can occur following intestinal perforation, particularly of the duodenum.

5. Pulmonary infection

Because the organism frequently colonizes the upper respiratory tract, it is commonly isolated from respiratory secretions. Thus, demonstration of tissue invasion is needed to diagnose Candida pneumonia or tracheitis. It is rare, seen mainly in immunosuppressed patients and patients intubated for long periods, usually while taking antibiotics. The infection may cause abscesses, nodular infiltrates, and effusion.

6. Renal infection

Candiduria may be the only manifestation of disseminated disease. Most often, candiduria is associated with instrumentation, an indwelling catheter, or anatomic abnormality of the urinary tract. Symptoms of cystitis may be present. Masses of Candida may obstruct ureters and cause obstructive nephropathy. Candida casts in the urine suggest renal tissue infection.

7. Other infections

Meningitis, and osteomyelitis usually occur only in immunocompromised patients or neonates, generally in those with high-grade candidemia. Endocarditis may occur on an artificial or abnormal heart valve, especially when an intravascular line is present.

8. Disseminated candidiasis

Skin and mucosal colonization precedes but does not predict dissemination. Too often, dissemination is confused with bacterial sepsis. This occurs in neonates—especially premature infants—in an intensive care unit setting and is recognized when a sick infant fails to respond to antibiotics or when candidemia is documented. Invasive disease can occur in greater than 50% of very low-birth-weight infants. These infants often have unexplained feeding intolerance, cardiovascular instability, apnea, new or worsening respiratory failure, glucose intolerance, thrombocytopenia, or hyperbilirubinemia. A careful search in immunocompromised patients should be carried out for lesions suggestive of disseminated Candida (retinal cotton-wool spots or chorioretinitis; nodular dermal abscesses). If these findings are absent, diagnosis is often based presumptively on the presence of a compatible illness in an immunocompromised patient; a burn patient; or a patient with prolonged postsurgical or intensive care unit course who has no other cause for symptoms and who fails to respond to antimicrobials. Such patients usually have Candida colonization of mucosal surfaces. Treatment for presumptive infection is often undertaken because candidemia is not identified antemortem in some such patients.

Hepatosplenic and renal candidiasis occurs in immunosuppressed patients. The typical case is a severely neutropenic patient who develops chronic fever, variable abdominal pain, and abnormal liver function tests. No causative bacterial pathogen is isolated, and there is no response to antimicrobials. Ultrasound or CT scan of the liver, spleen, and kidney demonstrates multiple round lesions. Biopsy is needed to confirm the diagnosis.

B. Laboratory Findings

Budding yeast cells are easily seen in scrapings or other samples. A wet mount preparation of vaginal secretions is 40%–50% sensitive; this is increased to 50%–70% with the addition of 10% potassium hydroxide to the sample. The use of a Gram-stained smear is 70%–100% sensitive. Stains for fungal cell walls will increase sensitivity. The presence of pseudohyphae suggests tissue invasion. Positive cultures from nonsterile sites may reflect colonization and need to be carefully evaluated, but Candida should never be considered a contaminant in cultures from normally sterile sites. Candida grows on routine media more slowly than many bacteria; growth is usually evident on agar after 2–3 days and in blood culture within 3 days, but cultures may remain negative (10%–40%) even with disseminated disease or endocarditis. The ability of yeast to form germ tubes when incubated in human serum gives a presumptive speciation for C albicans. However, newly available NMR (nuclear magnetic resonance) and PCR methods greatly shorten the delay in diagnosis and speciation. Candida in any number in appropriately collected urine suggests true infection.

Differential Diagnosis

Thrush may resemble milk or formula (which can be easily wiped away with a tongue blade or swab, revealing normal mucosa without underlying erythema or erosion), other types of ulcers (including herpes), or oral changes induced by chemotherapy. Skin lesions may resemble contact, allergic, chemical, or bacterial dermatitis; miliaria; folliculitis; or eczema. Vulvovaginitis needs to be distinguished from other causes of vaginal discharge and discomfort. Candidemia and systemic infection should be considered in any seriously ill patient with the risk factors previously mentioned.

Complications

Arthritis and meningitis occur more often in neonates than in older children, and abscesses can occur in any organ. The greater the length or extent of immunosuppression and the longer the delay before therapy, the more likely that complications will occur.

Treatment

A. Oral Candidiasis

In infants, oral nystatin suspension (100,000 units four to six times a day in the buccal fold after feeding for 2–3 days after resolution) usually suffices. Nystatin must come in contact with the lesions because it is not absorbed systemically. Older children may use it as a mouthwash (200,000–500,000 units five times a day), although it is poorly tolerated because of its taste. Clotrimazole troches (10 mg) four times a day are an alternative in older children. Prolonged therapy with either agent or more frequent dosing may be needed. Painting the lesions with a cotton swab dipped in gentian violet (0.5%–1%) is visually dramatic and messy but may help refractory cases. Eradication of Candida from pacifiers, bottle nipples, toys, or the mother’s breasts (if the infant is breast-feeding and there is candidal infection of the nipples) may be helpful.

Oral azoles, such as fluconazole (6 mg/kg/day), are effective in older children with candidal infection refractory to nystatin. Discontinuation of antibiotics or corticosteroids is advised when possible. Esophageal candidiasis should be treated with systemic therapy as described later.

B. Skin Infection

Cutaneous infection usually responds to a cream or lotion containing nystatin, amphotericin B, or an imidazole (miconazole, clotrimazole, naftidene, and others). Associated inflammation such as severe diaper dermatitis is helped by concurrent use of a topical low concentration corticosteroid cream, such as 1% hydrocortisone. It may help to keep the involved area dry; a heat lamp and nystatin powder may be used. Suppression of intestinal Candida with nystatin and eradicating thrush may speed recovery and prevent recurrence of diaper dermatitis.

C. Vaginal Infections

Vulvovaginal candidiasis (see Chapter 44) is treated with clotrimazole, miconazole, triazoles, or nystatin (cheapest if generic is used) suppositories or creams, usually applied once nightly for 3–7 days. A high-dose topical clotrimazole formulation can be given for only a single night. Oral azole therapy is equally effective. A single 150-mg oral dose of fluconazole is effective for vaginitis in older girls. It is more expensive but very convenient. Candida balanitis in sexual partners should be treated, but no controlled study has shown that treating colonization of male sexual partners prevents recurrence in females. Frequent recurrent infections (often with C glabrata) may require elimination of risk factors, the use of oral therapy, or some prophylactic antifungal therapy, such as a single dose of fluconazole weekly for 6 months.

D. Renal Infection

Candiduria in an immunocompetent host with a urinary catheter may respond to catheter removal. Candiduria is treated in all high-risk patients, usually with a 7- to 14-day course of fluconazole (3–6 mg/kg/day), which is concentrated in the urine. Amphotericin B is required for patients with fluconazole-resistant organisms. Renal abscesses or ureteral fungus balls require intravenous antifungal therapy. Removal of an indwelling catheter is imperative.

E. Systemic Infection

1. Disseminated Candida infection

Systemic infection is dangerous and resistant to therapy. Surgical drainage of abscesses and removal of all infected tissue (eg, a heart valve) are required for cure. An echinocandin is the preferred therapy. The initial dose and maintenance dosing varies with the drug chosen. Fluconazole may be substituted after 5–7 days if the response to therapy is satisfactory. Fluconazole as initial therapy is an alternative for selected patients who are not critically ill and who are likely to have a sensitive organism. Lipid formulations of amphotericin are alternatives when other drugs are not tolerated or when the isolate has an unfavorable resistance pattern. Hepatosplenic candidiasis should be treated until all lesions have disappeared or calcified.

Fluconazole and itraconazole (best absorbed from the liquid solution) and newer azole drugs, such as voriconazole and posaconazole, or echinocandins, are used interchangeably with or in conjunction with amphotericin. They are often preferred because they are less likely to be toxic than amphotericin. They are acceptable alternatives for serious C albicans infections in nonneutropenic patients and are often effective as first-line therapy in immunocompromised patients. The decision to use systemic azole therapy should include consideration of the local experience with azole-resistant Candida and if the patient had received prophylaxis or treatment with azoles. Fluconazole is well absorbed (oral and intravenous therapy are equivalent), reasonably nontoxic, and effective for a variety of Candida infections. Fluconazole dosage is 8–12 mg/kg/day in a single-daily dose for initial therapy of severely ill children. Selected patients with prolonged immunosuppression (eg, after hematopoietic stem cell transplantation) should receive prophylactic azole or echinocandin prophylaxis. Susceptibility testing for Candida species is available to guide this decision. Candida glabrata and C krusei are common isolates that may be resistant to fluconazole; these are often susceptible to the newer azoles and echinocandins. Candida lusitaniae is usually resistant to amphotericin. Many isolates of C auris are azole resistant; in the United States, most isolates remain susceptible to the echinocandins.

Correction of predisposing factors is important (eg, discontinuing antibiotics and immunosuppressives, improving control of diabetes, and removing infected devices and lines).

2. Candidemia

Infected central venous lines should be removed immediately; this alone often is curative. If the infection is considered limited to the line and environs, a 14-day course (after the last positive culture) of a systemic antifungal agent following line removal is recommended for nonneutropenic patients. An echinocandin is preferred, with completion of therapy with fluconazole when sensitivity is established. This is because of the late occurrence of focal Candida infection, especially retinal infection in some cases. Persistent fever and candidemia suggest infected thrombus, endocarditis, or tissue infection. All such patients should be examined by an ophthalmologist.

3. Very low-birth-weight infants

In many nurseries rates of severe Candida infection can exceed 5%–10%. Infected infants should receive intravenous amphotericin B (1 mg/kg/day) or fluconazole (12 mg/kg IV or PO) if no prior fluconazole. Treatment should continue until 2 weeks after the last positive culture. Lumbar puncture and eye examination should be performed. Prophylaxis in this setting is fluconazole (3 mg/kg twice weekly) for 6 weeks or until IV therapy is not needed.

Prognosis

Superficial disease in normal hosts has a good prognosis; in abnormal hosts, it may be refractory to therapy. Early therapy of systemic disease is often curative if the underlying immune response is adequate. The outcome is poor when therapy is delayed or when host response is inadequate. Candidemia in the severely premature neonate increases the chance of death and poor neurodevelopmental outcome.

Coccidioidomycosis

General Considerations

Coccidioidomycosis is caused by the dimorphic fungus Coccidioides (immitis or posadasii), which is endemic in the Sonoran Desert areas of western Texas, southern New Mexico and Arizona, southern California, northern Mexico, and South America. Infection results from inhalation or inoculation of arthrospores (highly contagious and readily airborne in the dry climate). Even brief travel in or through an endemic area, especially during windy seasons, may result in infection. Human-to-human transmission does not occur. More than 60% of infections are asymptomatic, and less than 5% are associated with significant pulmonary disease. Chronic pulmonary disease or dissemination occurs in less than 1% of cases.

Clinical Findings

A. Symptoms and Signs

1. Primary disease

The incubation period is 10–16 days (range, 7–28 days). Symptoms vary from those of a mild fever and arthralgia to severe influenza-like illness with high fever, nonproductive cough, pleuritic chest pains, arthralgias, headache, and night sweats. Upper respiratory tract signs are uncommon. Most infections are self-limited or minimal in severity. Signs vary from none to rash, rales, pleural rubs, and signs of pulmonary consolidation. Weight loss may occur.

2. Skin disease

Up to 10% of children develop erythema nodosum or erythema multiforme. These manifestations imply a favorable host response to the organism. Less specific maculopapular eruptions occur in a larger number of children. Skin lesions can occur following fungemia. Primary skin inoculation sites develop indurated ulcers with local adenopathy. Contiguous involvement of skin from deep infection in nodes or bone also occurs. The presence of chronic skin lesions should lead to a search for internal infection.

3. Chronic pulmonary disease

This is uncommon in children. Chronic disease is manifested by chronic cough (occasionally with hemoptysis), weight loss, and radiologic abnormalities.

4. Disseminated disease

This is less common in children than adults, and is more common in infants, neonates, pregnant women (especially during the third trimester), African Americans, Filipinos, American Indians, and patients with HIV or other defective T-cell–mediated immunity. More than one organ may be involved. The most common extrapulmonary sites involved are bone or joint (usually a single bone or joint; subacute or chronic swelling, pain, redness), nodes, meninges (slowly progressive meningeal signs, ataxia, vomiting, headache, and cranial neuropathies), and kidneys (dysuria and urinary frequency). As with most fungal diseases, the evolution of the illness is usually slow.

B. Laboratory Findings

Direct examination of respiratory secretions, pus, CSF, or tissue may reveal large spherules (30–60 μm) containing endospores germinating in tissue. The organism is detected by using periodic acid–Schiff reagent, methenamine silver, and calcofluor stains. Characteristic colonies grow within 2–5 days on routine fungal and many other media. CSF cultures are often falsely negative.

The sedimentation rate is usually elevated. Eosinophilia may occur, particularly prior to dissemination, and is more common in coccidioidomycosis than in many other conditions with similar symptoms. Meningitis causes a mononuclear pleocytosis (70% contain eosinophils) with elevated protein and mild hypoglycorrhachia.

Antibodies consist of precipitins (usually measurable by 2–3 weeks in 90% of cases and gone by 12 weeks) and complement-fixing antibodies (delayed for several weeks; appear as the precipitins are falling and should disappear by 8 months). Thus, serum precipitins usually indicate acute infection. The extent of the complement-fixing antibody response reflects the severity of infection. Persistent high levels suggest dissemination. ELISA assays, which detect IgM and IgG antibodies against coccidioidal antigens, become positive as early as 1–3 weeks (90% of positive tests) after onset of symptoms. The presence of antibody in CSF indicates CNS infection; CSF and serum antibody titers correlate with disease progression and response to therapy.

Galactomannan antigen from Coccidioides is detected in urine and serum of patients. This occurs more frequently in severe disease compared to moderate disease. Testing both urine and serum should provide a diagnosis in more than 75% of patients.

A skin test with coccidioides antigen can provide evidence of prior infection and conversion implies recent infection. A positive test is a good prognostic sign. Detection of coccidioidal antigen in CSF is useful to establish CNS infection.

C. Imaging

Approximately half of symptomatic infections are associated with abnormal chest radiographs—usually infiltrates with hilar adenopathy. Pulmonary consolidation, effusion, and thin-walled cavities may be seen. About 5% of infected patients have asymptomatic nodules or cysts after recovery. Unlike tuberculosis reactivation, apical disease is not prominent. Bone infection causes osteolysis that enhances with technetium. Cerebral imaging may show hydrocephalus and meningitis; intracranial abscesses and calcifications are unusual. Radiographic evolution of lesions is slow.

Differential Diagnosis

Primary pulmonary infection resembles acute viral, bacterial, or mycoplasmal infections; subacute presentation mimics tuberculosis, histoplasmosis, and blastomycosis. Chronic pulmonary or disseminated disease must be differentiated from cancer, tuberculosis, or other fungal infections.

Complications

Dissemination of primary pulmonary disease is associated with permissive ethnic background, prolonged fever (> 1 month), a negative skin test, high complement-fixation antibody titer, and marked hilar adenopathy. Pulmonary complications include effusion, empyema, and pneumothorax. Cerebral infection can cause noncommunicating hydrocephalus due to basilar meningitis.

Treatment

A. Specific Measures

Mild pulmonary infections in most immune competent patients do not require therapy, although some experts argue for treatment of all infections. Untreated patients should be assessed for 1–2 years to document resolution and to identify any complications. Antifungal therapy is used for prolonged fever, weight loss (> 10%), prolonged duration of night sweats, severe pneumonitis (especially if persisting for 4–6 weeks), or any form of disseminated disease. Neonates, pregnant women, high-risk racial background, and patients with high antibody titers also receive treatment.

Lipid formulation of amphotericin B is used to treat extensive pulmonary or disseminated disease or disease in immunosuppressed patients (2–5 mg/kg/day). In general, the more rapidly progressive the infection, the more compelling the case for amphotericin B therapy. For less severe disease and for meningeal disease, fluconazole or itraconazole is preferred (duration of therapy is 3–6 months or is lifelong for meningeal disease). Measurement of serum levels is suggested to monitor therapy. Chronic fibrocavitary pneumonia is treated for at least 12 months. Itraconazole may be superior to fluconazole. Refractory infection often responds to voriconazle together with caspofungin, and refractory meningitis may require prolonged intrathecal or intraventricular amphotericin B therapy.

B. General Measures

Most pulmonary infections require only symptomatic therapy, self-limited activity, and good nutrition. Patients are not contagious.

C. Surgical Measures

Excision of chronic pulmonary cavities or abscesses may be needed. Infected nodes, sinus tracts, and bone are other operable lesions. Azole therapy should be given prior to surgery to prevent dissemination and should be continued for 4 weeks arbitrarily or until other criteria for cure are met.

Prognosis

Most patients recover. Even with amphotericin B, however, disseminated disease may be fatal, especially in those racially predisposed to severe disease (African American, Filipino). A negative skin test or a rising complement-fixing antibody titer is an ominous sign. Individuals who later in life undergo immunosuppressive therapy or develop HIV may experience reactivation of dormant disease. Thus, some transplant, rheumatology, and oncology programs determine prior infection by serology and either provide prophylaxis or observe patients closely during periods of intense immune suppression.

Cryptococcosis

General Considerations

Cryptococcus neoformans is a ubiquitous soil yeast. It survives best in soil contaminated with bird excrement. However, most infections in humans are not associated with a history of significant contact with birds. Inhalation is the presumed route of inoculation. Infections in children are rare, even in heavily immunocompromised patients such as those with HIV infection. Immunocompetent individuals can also be infected, especially by Cryptococcus gattii, which is an emerging pathogen in Canada and the Pacific Northwest. Asymptomatic carriage does not occur.

Clinical Findings

A. Symptoms and Signs

1. Pulmonary disease

Pulmonary infection precedes dissemination to other organs. It is frequently asymptomatic (many older children and adults have serologic evidence of prior infection) and often not clinically apparent. Pneumonia is the primary manifestation in one-third of patients; CNS disease is the primary manifestation in 50% of patients. Cryptococcal pneumonia may coexist with CNS involvement. Symptoms are nonspecific and subacute—cough, weight loss, and fatigue.

2. Meningitis

The most common clinical disease is meningitis, which follows hematogenous spread from a pulmonary focus. This is much more likely to occur in an immunosuppressed patient (especially HIV). Symptoms of headache, vomiting, and fever occur over days to months. Meningeal signs and papilledema are common. Cranial nerve dysfunction and seizures may occur.

3. Other forms

Cutaneous disease is usually secondary to dissemination. Papules, pustules, and ulcerating nodules are typical. Bones (rarely joints) may be infected; osteolytic areas are seen, and the process may resemble osteosarcoma. Many other organs, especially the eyes, can be involved with dissemination.

B. Laboratory Findings

The CSF usually has a lymphocytic pleocytosis; it may be completely normal in immunosuppressed patients with meningeal infection. Direct microscopy may reveal organisms in sputum, CSF, or other specimens. The capsular antigen can be detected by latex agglutination or ELISA, which are both sensitive (> 90%) and specific. False-negative CSF tests are rare. Serum, CSF, and urine should be tested when this infection is suspected. The serum may be negative if the only organ infected is the lung. The organism grows well after several days on many routine media. For optimal culture, collecting and concentrating a large volume of CSF (10 mL) is recommended because the number of organisms may be low. Cryptococcus is included in some multiplex PCR panels for meningitis.

C. Imaging

Radiographic findings are usually lower lobe infiltrates or nodular densities; less often effusions; and rarely cavitation, hilar adenopathy, or calcification. Single or multiple focal mass lesions (cryptococcoma) may be detected in the CNS on CT or MRI scan.

Differential Diagnosis

Cryptococcal meningitis may mimic tuberculosis, viral meningoencephalitis, meningitis due to other fungi, or a space-occupying CNS lesion. Lung infection is difficult to differentiate from many causes of pneumonia.

Complications

Hydrocephalus may be caused by chronic basilar meningitis. Symptomatic and recalcitrant intracranial hypertension is common. Significant pulmonary or osseous disease may accompany the primary infection or dissemination.

Treatment

Patients with symptomatic pulmonary disease should receive fluconazole for 3–6 months. All immunocompromised patients with cryptococcal pulmonary disease should have a lumbar puncture to rule out CNS infection; this should also be done for immunocompetent patients with cryptococcal antigen in the serum. Severely ill patients should receive amphotericin B deoxycholate (1.0 mg/kg/day); lipid or liposomal formulations of amphotericin B may be equally effective with fewer side effects. Meningitis is treated with liposomal amphotericin B (3 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day) and flucytosine (100 mg/kg/day divided into four doses). Fluconazole may be substituted for flucytosine. Induction therapy is continued for a minimum of 2 weeks for CNS infections. Transition to consolidation therapy after this point depends on clinical response and measurement of cryptococcal antigen in CSF. Consolidation is with fluconazole alone (5 mg/kg BID) for 8 weeks followed by a reduced dose (maintenance therapy) for an additional 6–12 months. Some evidence suggests that voriconazole or posaconazole may have greater anticryptococcal activity. Fluconazole remains the preferred maintenance therapy to prevent relapses in high-risk (eg, HIV) patients. Intracranial hypertension is treated by frequent spinal taps or a lumbar drain.

Prognosis

Treatment failure, including death, is common in immunosuppressed patients, especially those with AIDS. Lifelong maintenance therapy may be required in these patients. Poor prognostic signs are the presence of extrameningeal disease, fewer than 20 cells/μL of initial CSF, and initial CSF antigen titer greater than 1:32.

Histoplasmosis

General Considerations

The dimorphic fungus Histoplasma capsulatum is found in the central and eastern United States (Ohio, Mississippi, and Missouri River valleys), Mexico, and most of South America. Soil contamination is enhanced by the presence of bat or bird feces. Infection is acquired by inhaling spores that transform into the pathogenic yeast form in infected tissues, especially within macrophages. Infections in endemic areas are very common at all ages and are usually asymptomatic. Over two-thirds of children are infected in these areas. Reactivation is rare in children, but occurs after treatment with immune suppressive agents, such as biological response modifiers and chemotherapy, even years after primary infection. Reinfection also occurs. The extent of symptoms with primary infection or reinfection is influenced by the size of the infecting inoculum.

Clinical Findings

Human-to-human transmission does not occur. Infection implies environmental exposure in an endemic area—usually within prior weeks or months. Congenital infection does not occur.

A. Symptoms and Signs

1. Asymptomatic infection (90% of infections)

Asymptomatic histoplasmosis is usually diagnosed by the presence of scattered calcifications in lungs or spleen and a positive skin test or serology. The calcification may resemble that caused by tuberculosis, but may be more extensive than the typical Ghon complex.

2. Pneumonia

Approximately 5% of patients have mild-to-moderate disease. The cause of this illness is usually not recognized as being histoplasma. Acute pulmonary disease may resemble influenza: fever, malaise, myalgia, arthralgia, and nonproductive cough occur 1–3 weeks after a heavy exposure (may be longer with less intense exposure). The subacute form resembles infections such as tuberculosis with cough, weight loss, night sweats, and pleurisy. Chronic disease is unusual in children. Physical examination may be normal, or rales may be heard. A small number of patients may have immune-mediated signs such as arthritis, pericarditis, and erythema nodosum. The usual duration of the disease is less than 2 weeks, followed by complete resolution, but without treatment, symptoms may last several months.

3. Disseminated infection (5% of infections)

Fungemia during primary infection probably occurs in the first 2 weeks of all infections, including those with minimal symptoms. Transient hepatosplenomegaly may occur, but resolution is the rule in immunocompetent individuals. Heavy exposure, severe underlying pulmonary disease, and immunocompromise are risk factors for progressive infection characterized by anemia, fever, weight loss, organomegaly, CNS or bone marrow involvement, and death. Dissemination may occur in otherwise immunocompetent children; usually they are younger than 2 years.

4. Other forms

Ocular involvement consists of multifocal choroiditis. This usually occurs in immunocompetent adults with other evidence of disseminated disease. Brain, pericardium, intestine, and skin (oral ulcers and nodules) are other sites that can be involved. Adrenal gland involvement is common with systemic disease.

B. Laboratory Findings

Routine tests are normal or nonspecific in the benign forms. Pancytopenia is present in many patients with disseminated disease. The diagnosis can be made by demonstrating the organism by histology or culture. Tissue yeast forms are small and may be mistaken for artifact. They are usually found in macrophages, occasionally in peripheral blood leukocytes in severe disease, but infrequently in sputum, urine, or CSF. Cultures of infected fluids or tissues may yield the organism after 1–4 weeks of incubation on fungal media, but even cultures of bronchoalveolar lavage or transbronchial biopsy specimens in immunocompromised patients are often negative (15%). Thus, bone marrow and tissue specimens are needed. Detection of histoplasmal antigen in blood, urine, CSF, and bronchoalveolar lavage fluid is the most sensitive diagnostic test (90% positive in the urine with disseminated disease, 75% positive with acute pneumonia), but false-negative results may occur. Cross-reactions occur with other fungal infections. Both urine and serum should be tested for optimal results. The level of antigen correlates with the extent of the infection, and antigen levels can be used to follow the response to therapy and to indicate low-grade infection persisting after completion of therapy (eg, in a child with HIV infection).

Antibodies may be detected by immunodiffusion and complement fixation; the latter rises in the first 2–6 weeks of illness and falls thereafter unless dissemination occurs. Cross-reactions occur with some other endemic fungi. A single high titer or rising titer indicates a high likelihood of disease, but antigen detection has replaced serology as a rapid diagnostic test.

C. Imaging

Scattered pulmonary calcifications in a well-child are typical of past infection. Bronchopneumonia (focal mid-lung infiltrates) occurs with acute disease, often with hilar and mediastinal adenopathy, occasionally with nodules, but seldom with effusion. Localized or patchy infiltrates occur in subacute disease. Apical cavitation occurs with chronic infection, often on the background of preexisting pulmonary infection.

Differential Diagnosis

Pulmonary disease resembles viral infection, other causes of community-acquired pneumonia, tuberculosis, coccidioidomycosis, and blastomycosis. Systemic disease resembles disseminated fungal or mycobacterial infection, leukemia, histiocytosis, or cancer.

Treatment

Most patients with acute pulmonary disease will benefit from oral itraconazole. Those with subacute disease are generally better when the diagnosis is established, but if still symptomatic should receive oral therapy. Treatment with lipid formulation of amphotericin B (2–5 mg/kg/day) is indicated for severe pulmonary disease (diffuse radiographic involvement); disseminated disease; or when endovascular, CNS, or chronic pulmonary disease is present; and for children younger than 1 year. Disseminated disease in infants may respond to as few as 10 days of amphotericin B, although 4–6 weeks is usually recommended. Patients with severe disease (especially pulmonary) may benefit from a short course of corticosteroid therapy. Surgical excision of chronic pulmonary lesions is rarely required. Itraconazole (3–5 mg/kg/day for 6–12 weeks; achieve peak serum level of > 1.0 mcg/mL) appears to be equivalent to amphotericin B therapy for mild disease and can be substituted in severe disease after a favorable initial (2 weeks) response to amphotericin B. Chronic pulmonary, CNS, or disseminated disease should be treated for at least a year after switching to oral drug.

Quantitation of fungal antigen is useful for directing therapy, and should be monitored for 1 year after successful treatment of severe disease. Relapse may occur in up to 15% of patients with treated chronic disease. Histoplasmosis can reactivate in previously infected individuals who subsequently become immunosuppressed. Chronically immunosuppressed patients may require lifelong maintenance therapy with itraconazole.

Prognosis

Patients with mild and moderately severe infections have a good prognosis. With early diagnosis and treatment, infants with disseminated disease usually recover; the prognosis worsens if the immune response is poor.

Sporotrichosis

General Considerations

Sporotrichosis is caused by S schenckii, a dimorphic fungus present as a mold in soil, plants, and plant products from most areas of North and South America. Spores of the fungus can cause infection when they breach the skin at areas of minor trauma. Sporotrichosis has been transmitted from cutaneous lesions of pets.

Clinical Findings

Cutaneous disease is by far the most common manifestation. Typically at the site of inapparent skin injury, an initial painless papular lesion will slowly become nodular and ulcerate. Subsequent new lesions develop in a similar fashion proximally along lymphatics draining the primary lesion. This sequence of developing painless, chronic ulcers in a linear pattern is strongly suggestive of the diagnosis. Solitary lesions may exist and some lesions may develop a verrucous character. Systemic symptoms are absent and laboratory evaluations are normal, except for acute-phase reactants. The fungus rarely disseminates in immunocompetent hosts. Cavitary pneumonia is a rare manifestation when patients inhale the spores. Immunocompromised patients, especially those with HIV infection, may develop disseminated skin lesions and multiorgan disease with extensive pneumonia.

Differential Diagnosis

The differential diagnosis of nodular lymphangitis (sporotrichoid infection) includes other endemic fungi and some bacteria, especially atypical mycobacteria and nocardiosis, pyoderma gangrenosum, and syphilis. Diagnosis is made by culture. Biopsy of skin lesions will demonstrate a suppurative response with granulomas and provides the best source for laboratory isolation. Occasionally, the characteristic yeast will be seen in the biopsy.

Treatment & Prognosis

Treatment is with itraconazole (200 mg/day or 5 mg/kg/day divided BID) for 2–4 weeks after lesions heal, usually 3–6 months. Prognosis is excellent with lymphocutaneous disease in immunocompetent children. Pulmonary or osteoarticular disease, especially in immunocompromised individuals, requires longer therapy. Amphotericin B may be required for disseminated disease, CNS disease, and severe pulmonary disease. Surgical debridement may be required.

PNEUMOCYSTIS & OTHER OPPORTUNISTIC FUNGAL INFECTIONS

The title of this section indicates that fungi that are normally not pathogenic, or do not cause severe disease, may do so when given the opportunity by changes in host defenses. They occur most commonly when patients are treated with corticosteroids, antineoplastic drugs, biological modifiers, or radiation, thereby reducing the number and function of neutrophils and B and T cells. Inborn errors in immune function (such as combined immunodeficiency or chronic granulomatous disease) may also be complicated by these fungal infections. Opportunistic infections are facilitated by altering the normal flora with antibiotics and by disruption of mucous membranes or skin with antineoplastic therapy or indwelling lines and tubes.

Table 43–5 indicates that filamentous fungi are prominent causes of severe systemic fungal disease in immunocompromised patients. Aspergillus species (usually fumigatus) and Zygomycetes (usually Mucorales) cause subacute pneumonia and sinusitis and should be considered when these conditions do not respond to antibiotics in immunocompromised patients. Aspergillus species also commonly cause invasive disease in patients with chronic granulomatous disease. Mucormycosis is especially likely to produce severe sinusitis in poorly controlled diabetics with acidosis. This fungus may invade the orbit and cause brain infection. Mucormycosis also occurs in patients receiving iron chelation therapy. These fungal infections may disseminate widely. Imaging procedures may suggest the etiology, but this is best diagnosed by aspiration or biopsy of infected tissues. A characteristic CT finding is the “halo sign,” which is a ground-glass opacity surrounding a pulmonary nodule or mass. The “reversed halo sign” is a focal rounded ground-glass opacity surrounded by a crescent or complete ring of consolidation. Detection of galactomannose and β-D-glucan in blood and alveolar fluid may be useful for the diagnosis of presumptive of aspergillosis and other opportunistic fungal pathogens.

Although Cryptococcus can cause disease in the immunocompetent hosts, it is more likely to be clinically apparent or more severe in immunocompromised patients. This yeast causes pneumonia and is a prominent cause of fungal meningitis (see earlier section in this chapter). Candida species in these patients cause fungemia and multiorgan disease, with lungs, esophagus, liver, and spleen frequently affected (see the earlier section on Disseminated Candida infection).

Opportunistic fungal infections should always be included in the differential diagnosis of unexplained fever or pulmonary infiltrates in immunocompromised patients. These pathogens should be aggressively pursued with imaging studies and with tissue sampling when clues are available. Cryptococcus and Aspergillus may be demonstrated with specific antigen tests. Aspergillus and mucorales can be suspected by detecting fungal cell wall components or by PCR. Interpretation of these results may be difficult, with greater uncertainty in pediatric patients. Opportunistic infections are difficult to treat because of the deficiencies in host immune response. Treatment should be undertaken with consultants who are expert in managing these infections. Voriconazole is the drug of choice for many mold infections, but both echinocandins and amphotericin B formulations are good alternatives in certain scenarios. Serum levels of voriconazole should be determined to guide therapy. Combinations of current antifungal drugs are being tested to improve the outcome. Many children who will have depressed phagocytic and T-cell–mediated immune function for long periods (eg, after hematopoietic stem cell transplants) should receive antifungal prophylaxis during the period of severe immune suppression, most often with fluconazole or itraconazole. Very low-birth-weight infants, who are at high risk for systemic Candida infection, often receive similar prophylaxis for prolonged periods.

Malassezia furfur is a yeast that normally causes the superficial skin infection known as tinea versicolor (see Chapter 15). This organism is considered an opportunist when fungemia is associated with prolonged intravenous therapy, especially with central lines used for hyperalimentation. The yeast, which requires skin lipids for its growth, can infect lines when lipids are present in the infusate. Some species will grow in the absence of lipids. Unexplained fever and thrombocytopenia are common. Pulmonary infiltrates may be present. The diagnosis is facilitated by alerting the bacteriology laboratory to add olive oil to culture media. The infection will respond to removal of the line or the lipid supplement. Amphotericin B may hasten resolution.

PNEUMOCYSTIS JIROVECI INFECTION

General Considerations

Although classified as a fungus on the basis of structural and nucleic acid characteristics, Pneumocystis responds readily to antiprotozoal drugs and antifolates. It is a ubiquitous pathogen. Initial infection is presumed to occur asymptomatically via inhalation, usually in early childhood, and to become a clinical problem upon reactivation associated with immune suppression. Person-to-person transmission may contribute to symptomatic disease in immunocompromised individuals. Clinical disease rarely occurs in the normal host. A syndrome of afebrile pneumonia similar to that caused by Chlamydia trachomatis in normal infants has been described, but its etiology is rarely appreciated. Whether by reactivation or new exposure, severe signs and symptoms occur chiefly in patients with abnormal T-cell function, such as hematologic malignancies and organ transplantation. Pneumocystis also causes severe pneumonia in patients with γ-globulin deficiency and is an AIDS-defining illness for children with advanced HIV infection. Prophylaxis usually prevents this infection (see Chapter 41).

Prolonged, high-dose corticosteroid therapy for any condition is a risk factor, with typical pneumonitis beginning as steroids are tapered.

Severely malnourished infants with no underlying illness may also develop this infection, as can those with congenital immunodeficiency. The incubation period is usually at least 1 month after onset of immunosuppressive therapy.

Clinical Findings

A. Symptoms and Signs

In most patients, a gradual onset of fever, tachypnea, dyspnea, and mild, nonproductive cough occurs over 1–4 weeks. Initially the chest is clear, although retractions and nasal flaring are present. At this stage the illness is nonspecific. Hypoxemia out of proportion to the clinical and radiographic signs is an early finding; however, even minimally decreased arterial oxygen pressure values should suggest this diagnosis in immunosuppressed children. Tachypnea, nonproductive cough, and dyspnea progress. Respiratory failure and death occur without treatment. In some children with AIDS or severe immunosuppression from chemotherapy or organ transplantation, the onset may be abrupt and progression more rapid. Acute dyspnea with pleuritic pain may indicate the complication of pneumothorax.

The general examination is unremarkable except for tachypnea and tachycardia; rales may be absent. There are no upper respiratory signs, conjunctivitis, organomegaly, enanthem, or rash.

B. Laboratory Findings

Laboratory findings reflect the individual child’s underlying illness and are not specific. Serum lactate dehydrogenase levels may be elevated markedly as a result of pulmonary damage. In moderately severe cases, the arterial oxygen pressure is less than 70 mm Hg or the alveolar-arterial gradient is less than 35 mm Hg.

C. Imaging

Early chest radiographs are normal. The classic pattern in later films is bilateral, interstitial, lower lobe alveolar disease starting in the perihilar regions, without effusion, consolidation, or hilar adenopathy. High-resolution CT scanning may reveal extensive ground-glass attenuation or cystic lesions. Older HIV-infected patients present with other patterns, including nodular infiltrates, lobar pneumonia, cavities, and upper lobe infiltrates.

D. Diagnostic Findings

Diagnosis requires finding characteristic round (6–8 mm) cysts in a lung biopsy specimen, bronchial brushings, alveolar washings, induced sputum, or tracheal aspirates. Tracheal aspirates are less sensitive, but are more rapidly and easily obtained. They are more often negative in children with leukemia compared with those with HIV infection; presumably, greater immunosuppression permits replication of a larger numbers of organisms. Because pneumonia in immunosuppressed patients may have many causes, negative results from tracheal secretions in suspected cases should prompt more aggressive diagnostic attempts. Bronchial washing using fiberoptic bronchoscopy is usually well tolerated and rapidly performed.

Several rapid stains—as well as the standard methenamine silver stain—are useful. The indirect fluorescent antibody method is most sensitive. These methods require competent laboratory evaluation, because few organisms may be present and many artifacts may be found. PCR methods are an important alternative.

Differential Diagnosis

In immunocompetent infants, C trachomatis pneumonia is the most common cause of the afebrile pneumonia syndrome described for Pneumocystis. In older immunocompromised children, the differential diagnosis includes influenza, respiratory syncytial virus, cytomegalovirus, adenovirus, and other viral infections; bacterial and fungal pneumonia; pulmonary emboli or hemorrhage; congestive heart failure; and Chlamydophila pneumoniae and Mycoplasma pneumoniae infections. Lymphoid interstitial pneumonitis, which occurs in older infants with untreated HIV infection, is more indolent and the patient’s lactate dehydrogenase level is normal (see Chapter 41). Pneumocystis pneumonia is rare in children who are complying with prophylactic regimens.

Prevention

Children at high risk for developing Pneumocystis infection should receive prophylactic therapy. Children at risk include those with hematologic malignancies, children who for other reasons are receiving intensive chemotherapy or high-dose corticosteroids, and children with organ transplants or advanced HIV infection. All children born to HIV-infected mothers should receive prophylaxis against Pneumocystis starting at age 6 weeks unless HIV infection has been ruled out by tests for HIV in serum. HIV-infected infants often receive therapy for the first year of life, or until the patient’s immunologic status is defined sufficiently to determine the need for additional prophylaxis (see Chapter 41). The prophylaxis of choice is trimethoprim-sulfamethoxazole (150 mg/m²/day of trimethoprim and 750 mg/m²/day of sulfamethoxazole) for 3 consecutive days of each week. Alternatives to this prophylaxis regimen for children who cannot tolerate trimethoprim-sulfamethoxazole include atovaquone, dapsone, or aerosolized pentamidine (https://aidsinfo.nih.gov/guidelines/html/5/pediatric-oi-prevention-and-treatment-guidelines/415/pneumocystis-jirovecii-pneumonia).

Treatment

A. General Measures

Supplemental oxygen and nutritional support may be needed. The patient should be in respiratory isolation.

B. Specific Measures

Trimethoprim-sulfamethoxazole (20 mg/kg/day of trimethoprim and 100 mg/kg/day of sulfamethoxazole in four divided doses intravenously or orally if well tolerated) is the treatment of choice. Improvement may not be seen for 3–5 days. Duration of treatment is 3 weeks in HIV-infected children. Methylprednisolone (2–4 mg/kg/day in four divided doses intravenously) should also be given to patients with moderate to severe infection (partial oxygen pressure < 70 mm Hg or alveolar-arterial gradient > 35) for the first 5 days of treatment. The dosage is reduced by 50% for the next 5 days and further by 50% until antibiotic treatment is completed. If trimethoprim-sulfamethoxazole is not tolerated or there is no clinical response in 5 days, pentamidine isethionate (4 mg/kg once daily by slow intravenous infusion) should be given. Clinical efficacy is similar with pentamidine, but adverse reactions are more common. These reactions include dysglycemia, pancreatitis, nephrotoxicity, and leukopenia. Other effective alternatives utilized in adults include atovaquone, trimethoprim plus dapsone, and primaquine plus clindamycin.

Prognosis

The mortality rate is high in immunosuppressed patients who receive treatment late in the illness.